Kathryn McGrath, MD

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; Kathryn.mcgrath@jefferson.edu.

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; Kathryn.mcgrath@jefferson.edu.

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; Kathryn.mcgrath@jefferson.edu.

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

[polldaddy:9781245]

How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; Kathryn.mcgrath@jefferson.edu.

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

[polldaddy:9781245]

How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; Kathryn.mcgrath@jefferson.edu.

CASE An 82-year-old woman with a history of hypertension, diabetes, hyperlipidemia, stage 3 chronic kidney disease, anxiety, urge urinary incontinence, constipation, and bilateral knee osteoarthritis presents to her primary care physician’s office after a fall. She reports that she visited the emergency department (ED) a week ago after falling in the middle of the night on her way to the bathroom. This is the third fall she’s had this year. On chart review, she had a blood pressure (BP) of 112/60 mm Hg and a blood glucose level of 65 mg/dL in the ED. All other testing (head imaging, chest x-ray, urinalysis) was normal. The ED physician recommended that she stop taking her lisinopril-hydrochlorothiazide (HCTZ) and glipizide extended release (XL) until her follow-up appointment. Today, she asks about the need to restart these medications.

Polypharmacy is common among older adults due to a high prevalence of chronic conditions that often require multiple medications for optimal management. Cut points of 5 or 9 medications are frequently used to define polypharmacy. However, some define polypharmacy as taking a medication that lacks an indication, is ineffective, or is duplicating treatment provided by another medication.

Either way, polypharmacy is associated with multiple negative consequences, including an increased risk for adverse drug events (ADEs),^1-4 drug-drug and drug-disease interactions (TABLE 1^5,6),⁷ reduced functional capacity,⁸ multiple geriatric syndromes (TABLE 2^5,9-12), medication non-adherence,¹³ and increased mortality.¹⁴ Polypharmacy also contributes to increased health care costs for both the patient and the health care system.¹⁵

Taking a step back. Polypharmacy often results from prescribing cascades, which occur when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom. Potentially inappropriate medications (PIMs), which are medications that should be avoided in older adults and in those with certain conditions, are also more likely to be prescribed in the setting of polypharmacy.¹⁶

Deprescribing is the process of identifying and discontinuing medications that are unnecessary, ineffective, and/or inappropriate in order to reduce polypharmacy and improve health outcomes. Deprescribing is a collaborative process that involves weighing the benefits and harms of medications in the context of a patient’s care goals, current level of functioning, life expectancy, values, and preferences. This article reviews polypharmacy and discusses safe and effective deprescribing strategies for older adults in the primary care setting.

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How many people on how many meds?

Polypharmacy often occurs when an adverse drug effect is misinterpreted as a new medical problem, leading to the prescribing of more medication to treat the initial drug-induced symptom.According to a 2016 study, 36% of community-dwelling older adults (ages 62-85 years) were taking 5 or more prescription medications in 2010 to 2011—up from 31% in 2005 to 2006.¹⁷ When one narrows the population to older adults in the United States who are hospitalized, almost half (46%) take 7 or more medications.¹⁸ Among frail, older US veterans at hospital discharge, 40% were prescribed 9 or more medications, with 44% of these patients receiving at least one unnecessary drug.¹⁹

The challenges of multimorbidity

In the United States, 80% of those 65 and older have 2 or more chronic conditions, or multimorbidity.²⁰ Clinical practice guidelines making recommendations for the management of single conditions, such as heart failure, hypertension, or diabetes, often suggest the use of 2 or more medications to achieve optimal management and fail to provide guidance in the setting of multimorbidity. Following treatment recommendations for multiple conditions predictably leads to polypharmacy, with complicated, costly, and burdensome regimens.

Further, the research contributing to the development of clinical practice guidelines frequently excludes older adults and those with multimorbidity, reducing applicability in this population. As a result, many treatment recommendations have uncertain benefit and may be harmful in the multimorbid older patient.²¹

CASE In addition to the patient’s multimorbidity, she had a stroke at age 73 and has some mild residual left-sided weakness. Functionally, she is independent and able to perform her activities of daily living and her instrumental activities of daily living. She lives alone, quit smoking at age 65, and has an occasional glass of wine during family parties. The patient’s daughter and granddaughter live 2 blocks away.

The goal of deprescribing is to reduce polypharmacy and improve health outcomes.

Her current medications include glipizide XL 10 mg/d and lisinopril-HCTZ 20-25 mg/d, which she has temporarily discontinued at the ED doctor’s recommendation, as well as: amlodipine 10 mg/d, metformin 1000 mg BID, senna 8.6 mg/d, docusate 100 mg BID, furosemide 40 mg/d, and ibuprofen 600 mg/d (for knee pain). She reports taking omeprazole 20 mg/d “for almost 20 years,” even though she has not had any reflux symptoms in recent memory. After her stroke, she began taking atorvastatin 10 mg/d, aspirin 81 mg/d, and clopidogrel 75 mg/d, which she continues to take today. About a year ago, she started oxybutynin 5 mg/d for urinary incontinence, but she has not noticed significant relief. Additionally, she takes lorazepam 1 mg for insomnia most nights of the week.

IMAGE: ©BRIAN STAUFER 2017

A review of systems reveals issues with chronic constipation and intermittent dizziness, but is otherwise negative. The physical examination reveals a well-appearing woman with a body mass index of 26. Her temperature is 98.5° F, her heart rate is 78 beats/min and regular, her respirations are 14 breaths/min, and her BP is 117/65 mm Hg. Orthostatic testing is negative. Her heart, lung, and abdominal exams are within normal limits. Her timed up and go test is 14 seconds. Her blood glucose level today in the office after eating breakfast 2 hours ago is 135 mg/dL (normal: <140 mg/dL). Laboratory tests performed at the time of the ED visit show a creatinine level of 1.2 mg/dL (normal range: 0.6 to 1.1 mg/dL), a glomerular filtration rate (GFR) of 44 units (normal range: >60 units), a hemoglobin level of 9.8 g/dL (normal range: 12-15.5 g/dL), and a thyroid stimulating hormone level of 1.4 mIU/L (normal range: 0.5-8.9 mIU/L). A recent hemoglobin A1C is 6.8% (normal: <5.7%), low-density lipoprotein (LDL) level is 103 mg/dL (optimal <100 mg/dL), and high-density lipoprotein (HDL) level is 65 mg/dL (optimal >60 mg/dL). An echocardiogram performed a year ago showed mild aortic stenosis with normal systolic and diastolic function.

Starting the deprescribing process: Several approaches to choose from

The goal of deprescribing is to reduce polypharmacy and improve health outcomes. It is a process defined as, “reviewing all current medications; identifying medications to be ceased, substituted, or reduced; planning a deprescribing regimen in partnership with the patient; and frequently reviewing and supporting the patient.”²² A medication review should include prescription, over-the-counter (OTC), and complementary/­alternative medicine (CAM) agents.

More than one-third of US men and women ages 62 to 85 years are taking 5 or more prescription medications.Until recently, studies evaluating the process of deprescribing across drug classes and disease conditions were limited, but new research is beginning to show its potential impact. After deprescribing, patients experience fewer falls and show improvements in cognition.²³ While there have not yet been large randomized trials to evaluate deprescribing, a recent systematic review and meta-analysis showed that use of patient-specific deprescribing interventions is associated with improved survival.²⁴ Importantly, there have been no reported adverse drug withdrawal events or deaths associated with deprescribing.²³

Smaller studies have reported additional benefits including decreases in health care costs, reductions in drug-drug interactions and PIMs, improvements in medication adherence, and increases in patient satisfaction.²⁵ In addition, the removal of unnecessary medications may allow for increased consideration of prescribing appropriate medications with known benefit.²⁵

Practically speaking, every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications. Electronic alert systems at pharmacies and those embedded within electronic health record (EHR) systems can also prompt a medication review and an effort to deprescribe.²⁶ Evidence-based tools to identify polypharm­acy and guide appropriate medication use are listed in TABLE 3.^5,6,27-30 In addition, suggested approaches to beginning the deprescribing process are included in TABLE 4.^5,31-33 And a medication class-based approach to deprescribing is provided in TABLE 5.^5,34-45

Although no gold standard process exists for deprescribing, experts suggest that any deprescribing protocol should include the following steps:^32,46

1. Start with a “brown bag” review of the patient’s medications.

Have the patient bring all of his/her medications in a bag to the visit; review them together or have the medication history taken by a pharmacist. Determine and discuss the indication for each medication and its effectiveness for that indication. Consider the potential benefits and harms of each medication in the context of the patient’s care goals and preferences. Assess whether the patient is taking all of the medications that have been prescribed, and identify any reasons for missed pills (eg, adverse effects, dosing regimens, understanding, cognitive issues).

2. Talk to the patient about the deprescribing process.

Talk with the patient about the risks and benefits of deprescribing, and prioritize which medications to address in the process. Prioritize the medications by balancing patient preferences with available pharmacologic evidence. If there is a lack of evidence supporting the benefits for a particular medication, consider known or suspected adverse effects, the ease or burden of the dosing regimen, the patient’s preferences and goals of care, remaining life expectancy, the time until drug benefit is appreciated, and the length of drug benefit after discontinuation.

3. Deprescribe medications.

If you are going to taper a medication, develop a schedule in partnership with the patient. Stop one medication at a time so that you can monitor for withdrawal symptoms or for the return of a condition.

Acknowledging potential barriers to deprescribing may help structure conversations and provide anticipatory guidance to patients and their families. Working to overcome these barriers will help maximize the benefits of deprescribing and help to build trust with patients.

Patient-driven barriers include fear of a condition worsening or returning, lack of a suitable alternative, lack of ongoing support to manage a particular condition, a previous bad experience with medication cessation, and influence from other care providers (eg, family, home caregivers, nurses, specialists, friends). Patients and family members sometimes cling to the hope of future effectiveness of a treatment, especially in the case of medications like donepezil for dementia.⁴⁷ Utilizing a team-based and stepwise patient approach to deprescribing aims to provide hesitant patients with appropriate amounts of education and support to begin to reduce unnecessary medicines.

Provider-driven barriers include feeling uneasy about contradicting a specialist’s recommendations for initiation/continuation of specific medications, fear of causing withdrawal symptoms or disease relapse, and lack of specific data to adequately understand and assess benefits and harms in the older adult population. Primary care physicians have also acknowledged worry about discussing life expectancy and that patients will feel their care is being reduced or “downgraded.”⁴⁸ Finally, there is limited time in which these complex shared decision-making conversations can take place. Thus, if medications are not causing a noticeable problem, it is often easier to just continue them.

Every encounter between a patient and health care provider is an opportunity to reduce unnecessary medications.

One way to overcome some of these concerns is to consider working with a clinical pharmacist. By gaining information regarding medication-specific factors, such as half-life and expected withdrawal patterns, you can feel more confident deprescribing or continuing medications.

Additionally, communicating closely with specialists, ideally with the help of an integra­ted EHR, can allow you to discuss indications for particular medications or concerns about adverse effects, limited benefits, or difficulty with compliance, so that you can develop a collaborative, cohesive, and patient-centered plan. This, in turn, may improve patient understanding and compliance.

4. Create a follow-up plan.

At the time of deprescribing a medication, develop a plan with the patient for monitoring and assessment. Ensure that the patient understands which symptoms may occur in the event of drug withdrawal and which symptoms may suggest the return of a condition. Make sure that other supports are in place if needed (eg, cognitive behavioral therapy, physical therapy, social support or assistance) to help ensure that medication cessation is successful.

CASE During the office visit, you advise the patient that her BP looks normal, her blood sugar is within an appropriate range, and she is lucky to have not sustained any injuries after her most recent fall. In addition to discussing the benefits of some outpatient physical therapy to help with her balance, you ask if she would like to discuss reducing her medications. She is agreeable and asks for your recommendations.

You are aware of several resources that can help you with your recommendations, among them the STOPP/START⁶ and Beers criteria,⁵ as well as the Good Geriatric-Palliative Algorithm.³⁰

If you were to use the STOPP/START and Beers criteria, you might consider stopping:

• lorazepam, which increases the risk of falls and confusion.
• ibuprofen, since this patient has only mild osteoarthritis pain, and ibuprofen has the potential for renal, cardiac, and gastrointestinal toxicities.
• oxybutynin, because it could be contributing to the patient’s constipation and cause confusion and falls.
• furosemide, since the patient has no clinical heart failure.
• omeprazole, since the indication is unknown and the patient has no history of ulceration, esophagitis, or symptomatic gastroesophageal reflux disease.

After reviewing the Good Geriatric-Palliative Algorithm,³⁰ you might consider stopping:

• clopidogrel, as there is no clear indication for this medication in combination with aspirin in this patient.
• glipizide XL, as this patient’s A1c is below goal and this medication puts her at risk of hypoglycemia and its associated morbidities.
• metformin, as it increases her risk of lactic acidosis because her GFR is <45 units.
• docusate, as the evidence to show clear benefit in improving chronic constipation in older adults is lacking.

There have been no reported adverse drug withdrawal events or deaths associated with deprescribing.

You tell your patient that there are multiple medications to consider stopping. In order to monitor any symptoms of withdrawal or return of a condition, it would be best to stop one at a time and follow-up closely. Since she has done well for the past week without the glipizide and lisinopril-HCTZ combination, she can remain off the glipizide and the HCTZ. Lisinopril, however, may provide renal protection in the setting of diabetes and will be continued at this time.

You ask her about adverse effects from her other medications. She indicates that the furosemide makes her run to the bathroom all the time, so she would like to try stopping it. You agree and make a plan for her to monitor her weight, watch for edema, and return in 4 weeks for a follow-up visit.

On follow-up, she is feeling well, has no edema on exam, and is happy to report her urinary incontinence has resolved. You therefore suggest her next deprescribing trial be discontinuation of her oxybutynin. She thanks you for your recommendations about her medications and heads off to her physical therapy appointment.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Division of Geriatric Medicine and Palliative Care, Thomas Jefferson University, 2422 S Broad St, 2nd Floor, Philadelphia, PA 19145; Kathryn.mcgrath@jefferson.edu.