Acute Migraine Treatment in Emergency Settings Prepared for: Agency for Healthcare Research and...

Acute Migraine Treatmentin Emergency Settings

Prepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Agency for Healthcare Research and Quality Comparative Effectiveness Review (CER) Process

Background Clinical Questions Addressed in the CER Summary of CER Results Conclusions Gaps in Knowledge Resources for Shared Decisionmaking

Outline of Material

Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www.effectivehealthcare.ahrq.gov/migraine-emergency.cfm.

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue.

The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into a Clinician Research Summary and a Consumer Research Summary for use in decisionmaking and in discussions with patients.

The Research Summaries and the full report are available at www.effectivehealthcare.ahrq.gov/migraine-emergency.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


The strength-of-evidence ratings are classified into four broad ratings:

Strength-of-Evidence Ratings

AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol. 2010 May;63(5):513-23. PMID: 19595577.Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www.effectivehealthcare.ahrq.gov/migraine-emergency.cfm.

Migraine is a primary headache disorder, which may be associated with abnormalities of the central and peripheral nervous systems and the intracranial vasculature.

In 2010, migraine was the third most prevalent disorder and seventh highest specific cause of disability worldwide.

Migraine affects 12 percent of the population in the United States.

Background: Migraine Headaches

Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):629-808. PMID: 23771276.Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www.effectivehealthcare.ahrq.gov/migraine-emergency.cfm.

Migraines are classified using criteria established by the International Headache Society within the International Classification of Headache Disorders (ICHD). Migraine with aura: a migraine headache preceded or

accompanied by an “aura” (e.g., a set of self-limited sensory [visual, tactile, and/or olfactory] symptoms)

Migraine without aura: the most common type of migraine and often more disabling than migraines with aura

Chronic migraine: a migraine headache that occurs on > 15 days per month for at least 3 months

Background: Classification of Migraine Headaches

Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):629-808.

Diagnostic CriteriaA. At least two attacks fulfilling criteria B and CB. One or more of the following fully reversible aura symptoms:

1. Visual2. Sensory3. Speech and/or language4. Motor5. Brainstem6. Retinal

C. At least two of the following four characteristics:1. At least one aura symptom spreads gradually over 5 minutes,

and/or two or more symptoms occur in succession2. Each individual aura symptom lasts 5–60 minutes3. At least one aura symptom is unilateral4. The aura is accompanied, or followed within 60 minutes, by

headache

D. Have a headache not better accounted for by another ICHD-3 diagnosis and a transient ischemic attack has been excluded

Background: Migraine With Aura

Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):629-808.PMID: 23771276.

Diagnostic CriteriaA. At least five attacks fulfilling criteria B, C, and D

B. Attacks lasting 4–72 hours (untreated or unsuccessfully treated)

C. At least two of these characteristics:

1. Unilateral location

2. Pulsating quality

3. Moderate or severe intensity

4. Aggravation by or causing avoidance of routine physical activity

D. At least one of the following during headache:

1. Nausea and/or vomiting

2. Photophobia and phonophobia

E. Not better accounted for by another ICHD-3 diagnosis

Background: Migraine Without Aura

Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):629-808. PMID: 23771276.

Diagnostic CriteriaA. Headache occurring on 15 or more days per month for more

than 3 months, which has the features of migraine headache on at least 8 days per month

B. A tension-like and/or migraine-like headache on 15 days per month for >3 months and fulfill criteria 1 and 21. Occurring in a patient who has had at least five attacks fulfilling

criteria B, C, and D for migraine without aura and/or criteria B and C for migraine with aura

2. On 8 days per month for >3 months, fulfilling any of the following:

a. Criteria C and D for migraine without aura

b. Criteria B and C for migraine with aura

c. Believed by the patient to be migraine at onset and is relieved by a triptan or an ergot derivative

C. Not better accounted for by another ICHD-3 diagnosis

Background: Chronic Migraine

Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33(9):629-808. PMID: 23771276.

A severe headache associated with disabling pain may result in a visit to an emergency department (ED).

Headaches account for 2.1 million ED visits, or 2.2 percent of all ED visits, annually in the United States.

About 7 percent of Americans with migraine have used an ED or urgent care center for treatment of severe headache within the previous 12 months.

Of patients who use an ED for treatment of migraine, 19 percent make multiple visits over the course of 1 year.

Background: Incidence of Migraine Headaches Leading to Emergency Department Visits in the United States

Hu XH, Markson LD, Lipton RB, et al. Arch Intern Med. 1999;159(8):813-8. PMID: 10219926.Lambert J, Carides GW, Meloche JP, et al. Can J Clin Pharmacol. 2002;9(3):158-64. PMID: 12422253.

Migraine has a negative impact on overall quality of life and is associated with: Decreased productivity Missed time from work, school, and other activities Medical comorbidities

In the United States, migraine and related medical issues result in costs of more than $13 billion per year due to lost productivity.

In Canada, this annual cost has been estimated at $3,025 per patient due to medical and indirect costs.

Background:Economic Burden of Migraine Headaches

Bamford CC, Tepper SJ. Tech Reg Anesth Pain Manag. 2009;13(1):20-7. DOI: 10.1016/j.bbr.2011.03.031.Bigal ME, Ferrari M, Silberstein SD, et al. Headache. 2009;49 Suppl 1:S21-S33. PMID: 19161562.Cutrer FM. Semin Neurol. 2010;30(2):120-30. PMID: 20352582. Diamond S, Bigal ME, Silberstein S, et al. Headache. 2007;47(3):355-63. PMID: 17371352.Headache Classification Committee of the International Headache Society. Cephalalgia.2004;24(Suppl 1):629-808. PMID: 23771276.

Substantial practice variability exists among emergency departments (EDs) and emergency clinicians.

Approximately 20 different parenteral agents are used to treat acute migraine in EDs.

Some physicians use agents in sequence; others use combination treatments.

Background:Treatment of Migraine in the Emergency Setting


Drug Class Pharmacological Interventions in Each Drug Class

Antiemetics/neuroleptics

chlorpromazine*, droperidol*, haloperidol*, metoclopramide*, prochlorperazine*, and trimethobenzamide*

Corticosteroids betamethasone, budesonide, cortisone, dexamethasone*, hydrocortisone, methylprednisolone, prednisolone, and prednisone*

Ergots Dihydroergotamine (DHE)*

Nonsteroidal anti-inflammatory drugs

diclofenac*, ibuprofen, ketorolac*, and lysine clonixinate*

Opioids butorphanol*, buprenorphine, fentanyl, hydromorphone, meperidine (pethidine)*, morphine*, nalbuphine*, and tramadol*

Triptans sumatriptan*

Other agents dimenhydrinate *, hydroxyzine*, lidocaine*, olanzapine*, ondansetron*, and promethazine*

*These interventions were studied in the trials included in the systematic review.

Background: Summary of Pharmacological Interventions Used To Treat Acute Migraine


To assess the effectiveness and adverse effects of parenteral medications for adult patients with moderate to severe acute migraine who present to an emergency department (ED) for treatment

To examine the benefits and adverse effects of using corticosteroids to prevent recurrence of acute migraine that results in a return visit to a physician or an ED

Objectives of the Systematic Review


The comparative effectiveness of parenteral pharmacological interventions versus standard care, placebo, or an active treatment

The comparative effectiveness of adding parenteral or oral corticosteroids versus adding placebo to prevent recurrence of acute migraine

The associated and comparative short-term adverse effects of these interventions

The effectiveness and safety of these interventions in different subgroups

Key Questions Regarding Treatment of Acute MigraineHeadaches in the Emergency Setting


Outcomes of Interest Benefits

Pain relief (complete or partial)/change in pain score

Elimination of pain before emergency department (ED) discharge

Time in the ED (in minutes of total time and post-ED physician time)

Recurrence of headache (headache relieved in the ED and recurring within the followup period)

Health services utilization Patient satisfaction with

experience Quality of life/return to activities

Adverse Effects (up to 3 months after intervention) Sedation/somnolence Dizziness Restless legs/akathisia Anxiety Vomiting Chest symptoms (e.g.,

palpitations) Skin flushing Local reactions Other side effects


Overview of Studies Included in theSystematic Review


The majority of studies used the visual analog scale (VAS) to assess pain.

When pain scores were reported in any format other than VAS (in mm), they were converted to a VAS scale (in mm) using a conversion factor.

All pain scales were subjective and anchored by “severe” and “zero” extremes.

Conversion to a 100-point scale was used for comparative purposes across trials.

Changes in pain intensity are reported as the mean difference when compared with placebo or another intervention on a 100-point VAS (in mm).

Overview of Studies: Assessing Pain Across Trials That Use Different Pain Scales


Neuroleptics, nonsteroidal anti-inflammatory drugs, and sumatriptan improve the likelihood of achieving pain-free status at various time points after administration versus placebo.

Clinical Bottom Line: Efficacy of Interventions for Achieving “Pain-Free” Status Versus Placebo

Medication

Time Points Taken in

ED

Relative Risk(95% CI)

Strength of Evidence

Sumatriptan 30 to 120 min

4.73 (3.77 to 5.94)

Moderate

Neuroleptics* 60 min 3.38 (1.16 to 9.83)

Moderate

NSAIDs 60 to 120 min

2.74 (1.26 to 5.98)

Moderate

*Neuroleptics here include chlorpromazine, droperidol, and prochlorperazine.95% CI = 95-percent confidence interval; NSAIDs = nonsteroidal anti-inflammatory drugs; ED = emergency department


More patients report full relief from headaches with droperidol when compared with prochlorperazine (relative risk = 0.81; 95-percent confidence interval 0.68 to 0.98).

Strength of Evidence = Moderate

The evidence is insufficient to permit conclusions about the comparative effectiveness of other interventions.

Clinical Bottom Line: Comparative Effectiveness of Interventions for Achieving a “Pain-Free” Status


Neuroleptics and sumatriptan provide significant headache relief at various time points versus placebo.

Clinical Bottom Line: Efficacy of Interventions for Providing Headache Relief (Complete or Partial) Versus Placebo

MedicationTime

Points Taken in

ED

Relative Risk(95% CI)

Strength of

Evidence

Neuroleptics*

60 min 2.69 (1.66 to 4.34) Moderate

Sumatriptan 60 min 3.03 (2.59 to 3.54) Moderate

Sumatriptan 120 min 2.61 (2.09 to 3.26) Moderate*Neuroleptics here include haloperidol, chlorpromazine, prochlorperazine, and droperidol.95% CI = 95-percent confidence interval; ED = emergency department


Neuroleptics, metoclopramide, opioids, and sumatriptan significantly improve pain intensity (as measured on a visual analog scale [VAS] in mm) at various time points versus placebo.

Clinical Bottom Line: Efficacy of Interventions for Reducing Pain Intensity (VAS in mm)

MedicationTime Points

in ED

Mean Difference in Visual

Analog Scale in Millimeters

(95% CI)

Strength of

Evidence

Neuroleptics* 30 min to 4 hrs

-46.59 (-54.87 to -38.32) Moderate

Metoclopramide

30 to 60 min -21.88 (-27.38 to -16.38) Moderate

Opioids** 45 to 60 min -16.73 (-24.12 to -9.33) Moderate

Sumatriptan 30 min -15.45 (-19.49 to -11.41) Moderate

*Neuroleptics here include prochlorperazine, chlorpromazine, and haloperidol.**Opioids here include pethidine, nalbuphine, tramadol, and hydroxyzine + nalbuphine.95% CI = 95-percent confidence interval; ED = emergency department


Neuroleptics (chlorpromazine and prochlorperazine) as a group reduce pain intensity more than metoclopramide (mean difference = 16.45 mm; 95-percent confidence interval 2.08 to 30.83).Strength of Evidence = Low

There are no differences in the reduction of pain intensity when metoclopramide and prochlorperazine are compared alone.Strength of Evidence = Low

There are no significant differences in the reduction in pain between prochlorperazine and droperidol.Strength of Evidence = Low

Clinical Bottom Line: Comparative Effectiveness of Interventions for Reducing Pain Intensity (VAS in mm*)

*Pain was measured on a visual analog scale (VAS) in millimeters.


Recurrence occurs when a patient’s headache is successfully relieved in the emergency department and then comes back within the followup period.

Dexamethasone plus standard abortive therapy is less likely to result in recurrence of pain or headache up to 72 hours after discharge when compared with placebo plus standard abortive therapy (relative risk [RR] = 0.68, 95-percent confidence interval [95% CI] 0.49 to 0.96). Strength of Evidence = Moderate

Sumatriptan may have a lower rate of headache recurrence within 24 hours versus placebo (RR = 0.72, 95% CI 0.57 to 0.90). Strength of Evidence = Low

Evidence on recurrence rates for other interventions is insufficient to permit conclusions.

Clinical Bottom Line: Preventing Recurrence


Improvement in pain intensity is greatest with combination therapy (dihydroergotamine added to either prochlorperazine or metoclopramide) and neuroleptic monotherapy, with a reduction of about 40 mm on a visual analog scale (VAS; 95-percent confidence intervals [95% CIs] ranging from 60.9 to 22.1). Strength of Evidence = Low

Metoclopramide, opioids, and nonsteroidal anti-inflammatory drugs are the next most effective treatments, with a pain reduction of about 24 mm on the VAS (95% CIs ranging from 38.8 to 12.0). Strength of Evidence = Low

Clinical Bottom Line: Indirect Comparisons Across Trials for Reducing Pain Intensity (1 of 2)


Dihydroergotamine monotherapy, sumatriptan, and orphan agents are less effective, with a pain reduction of approximately 12 to 16 mm on the visual analog scale (95-percent confidence intervals ranging from 32.6 to 0.5). Strength of Evidence = Low

No statistically significant difference in effect on pain intensity is noted for other antinauseants. Strength of Evidence = Low

Clinical Bottom Line: Indirect Comparisons Across Trials for Reducing Pain Intensity (2 of 2)


Akathisia is a state of restlessness or agitation. It can be described as a feeling of muscle quivering. It can occur at any time and more often when a sufferer is sitting.

Akathisia is usually self-limited but creates patient discomfort and distress.

The risk of akathisia after taking a neuroleptic agent or metoclopramide was about 10 times greater than with placebo.

Clinical Bottom Line: Adverse Effects—Akathisia

No strength-of-evidence rating is associated with any of these results.


Evidence is insufficient to determine which treatment(s) result in more or less adverse effects.

Rates of adverse effects are reported without strength-of-evidence ratings.

The risk of sedation was common after receiving metoclopramide or prochlorperazine (17% for both).

The most common adverse effects from dihydroergotamine included pain or swelling at the injection site, IV site irritation, sedation, digestive issues, nausea or vomiting, and chest symptoms (palpitations, arrhythmia, or irregular heartbeat).

Clinical Bottom Line:Adverse Effects—General (1 of 2)


The most common adverse effects of injectable triptans are local reactions including pain or swelling at the injection site.

According to the U.S. Food and Drug Administration, there is a risk of coronary vasospasm if sumatriptan is given to patients with known or unknown coronary or vascular risk factors.

Few short-term effects were reported for nonsteroidal anti-inflammatory drugs.

The risk with opioids is associated with continuing or frequent use, which can lead to dependency.

Clinical Bottom Line:Adverse Effects—General (2 of 2)


Several common parenteral treatments for migraine pain (e.g., sumatriptan, metoclopramide, neuroleptics, and nonsteroidal anti-inflammatory drugs) in emergency departments are effective at reducing pain intensity and/or achieving pain-free status.

Direct head-to-head comparisons are very limited; however, moderate-strength evidence suggests that droperidol may provide full headache relief better than prochlorperazine.

Low-strength evidence from indirect comparisons made across trials using statistical techniques to assess pain reduction suggests that dihydroergotamine, in combination with either prochlorperazine or metoclopramide, and neuroleptic monotherapy are the most effective (approximately a 40-mm reduction on a 100-point visual analog scale).

Patients who receive dexamethasone plus abortive therapy are less likely to have a recurrence of a migraine.

Overview of Conclusions


Most adverse effects are minor and self-limiting. Data on pain relief must be weighed carefully with

the data on side effects, especially akathisia, which is associated more with the neuroleptics and metoclopramide.

Overview of Adverse Effects


The systematic review identified several areas where future research will help to address the gaps in clinical knowledge. Additional studies are needed in these areas: Head-to-head comparisons to determine which

treatments are most effective in quickly reducing migraine pain, achieving pain-free status, and reducing the likelihood of relapse

The effects of sex, race, and duration of headache on the response to treatment

The differences in effectiveness among different parenteral delivery routes (intravenous, intramuscular, and subcutaneous)

Gaps in Knowledge


Effectiveness of chosen treatments Evidence of adverse effects Reasons for using combination therapy Use of dexamethasone to prevent relapse The availability of treatments for chronic migraine

to prevent recurrent emergency treatment

Shared Decisionmaking: What To Discuss With Your Patients


Resource for Patients Treating Severe Migraine

Headaches in the Emergency Room, A Review of the Research for Adults is a free resource that can help patients talk with their health care professionals about treatment options. It provides information about: Migraine headaches Benefits and possible side

effects of migraine headache treatments

Questions to discuss with their doctor Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review

No. 84. Available at www.effectivehealthcare.ahrq.gov/migraine-emergency.cfm.

Acute Migraine Treatment in Emergency Settings Prepared for: Agency for Healthcare Research and...

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