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Original Article

Metoclopramide and Diphenhydramine: A Randomized


Controlled Trial of a Treatment for Headache in
Pregnancy when Acetaminophen Alone Is
Ineffective (MAD Headache Study)
Katherine M. Scolari Childress, MD1 Christina Dothager, MD1 Jeffrey A. Gavard, PhD1
Sara Lebovitz, MD1 Catherine Laska, MD1 Dorothea J. Mostello, MD1

1 Division of Maternal-Fetal Medicine, Department of Obstetrics, Address for correspondence Katherine M. Scolari Childress, MD,
Gynecology, and Women’s Health, Saint Louis University School of Division of Maternal-Fetal Medicine, Department of Obstetrics,
Medicine, St. Louis, Missouri Gynecology, and Women’s Health, Saint Louis University School of
Medicine, 6420 Clayton Road, Suite 2800, St. Louis, MO 63117
Am J Perinatol (e-mail: kmschildress@gmail.com).

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Abstract Objective We investigated whether metoclopramide administered with diphenhy-
dramine (MAD) relieves headache in pregnant women when acetaminophen alone is
ineffective, using codeine for comparison.
Study Design Normotensive pregnant women in the second or third trimester were
randomized to MAD intravenously (10 mg and 25 mg, respectively) or codeine orally
(30 mg) for headache after 650 to 1,000 mg of acetaminophen failed to relieve their
headaches. Headache severity (pain score 0–10) was noted at intervals over 24 hours. The
primary outcome was reduction in pain score 6 hours after medication administration. A
sample size calculation of 35 patients per group was based on estimated reduction in
headache pain score by at least two points, with an α of 0.05 and a power of 80%.
Results No difference was seen in the primary outcome. MAD pain scores were lower
at 30 minutes (3  2.8 versus 5.8  2.3, p < 0.001), 1 hour (2.2  2.3 vs. 4.1  3;
Keywords p < 0.01), and 12 hours (1.3  2.5 vs. 2.7  3; p < 0.05), but not at 6 hours. Time to
► headache perceived headache relief was shorter for MAD than for codeine (20.2  13.4 vs.
► pregnancy 62.4  62.2 minutes; p < 0.001). More patients in the MAD group reported full
► metoclopramide headache relief within 24 hours (76.5 vs. 37.5%; p < 0.01).
► diphenhydramine Conclusion MAD effectively relieves headaches in pregnant women when acetami-
► codeine nophen fails.

Headache is a common problem during pregnancy, estimated controversial. Opiates, nonsteroidal anti-inflammatory drugs,
to occur in more than 20% of patients.1,2 Pharmacological and triptans are used; however, concern exists regarding the
treatment can be challenging with little evidence-based treat- safety of these medications during pregnancy. Opiates also
ment and most recommendations based on studies in non- pose potential for abuse, maternal dependence, and neonatal
pregnant patients, involving medications that are felt to be safe withdrawal. Thus, common second-line agents may be
during pregnancy. Generally, acetaminophen is first-line med- avoided, leaving limited options in the treatment of headache
ication in the treatment of headaches in pregnancy, as it is felt during pregnancy.1–4,10
to be generally safe, is low in cost, and has few side effects.3–9 Some antiemetics, often in combination with antihista-
Second-line treatment when acetaminophen fails is more mines, have been shown to possess pain-reducing qualities

received Copyright © by Thieme Medical DOI https://doi.org/


September 18, 2017 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1646952.
accepted after revision New York, NY 10001, USA. ISSN 0735-1631.
March 21, 2018 Tel: +1(212) 584-4662.
Metoclopramide and Diphenhydramine Childress et al.

in addition to their antinausea effects, and several rando- severe pain, was used to determine medication effectiveness
mized controlled trials have shown their effectiveness as over a 24-hour period (at baseline, 30 minutes, 1 hour,
headache treatment medications in nonpregnant 6 hours, 12 hours, and 24 hours) after administration of
patients.11–13 Metoclopramide has been shown to be effec- the first dose of study medication. Patients were asked a
tive in the treatment of headaches in emergency department series of questions regarding their experience at the 24-hour
settings.14–16 It is widely used in the treatment of nausea and assessment. The primary outcome was a reduction in pain
vomiting of pregnancy and data support its safety even in the score by at least two points 6 hours after medication admin-
first trimester of pregnancy.14–17 Diphenhydramine is often istration.19–21 Secondary outcomes were differences in
combined with metoclopramide for its sedating properties headache scores at the other time assessments, whether
and to prevent akathisia reactions. Both medications are low patients required additional doses of the study medication or
in cost, are widely available, and considered safe in preg- another nonstudy drug and whether patients experienced
nancy. Although they have shown promise in the treatment headache recurrence, side effects, and other subjective
of headaches in nonpregnant patients, their effectiveness in assessments of patient experience.
the treatment of headaches has not been studied in a A sample size calculation of 35 patients in each group was
pregnant population. based on an estimated reduction in headache pain score by at
The objective of our study was to investigate whether least two points, with an α of 0.05 and a power of 80%, which
treatment with a combination of intravenous (IV) metoclo- is similar to estimates reported in prior studies in nonpreg-
pramide and diphenhydramine (MAD) effectively relieves nant patients and felt to be a clinically significant
headache in pregnant patients when acetaminophen alone decrease.19–23 Statistical analyses were performed using

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is ineffective, using codeine as the standard for comparison. chi-square test and Fisher’s exact test for categorical vari-
We hypothesized that treatment with MAD would be as ables, and independent Student’s t-test and Mann–Whitney
effective as codeine for the relief of headaches in a pregnant U test for continuous variables, as appropriate. Mixed models
population. repeated measures analysis of variance was used to assess an
interaction effect of headache pain scores. A p-value of <0.05
was used to indicate statistical significance. Analyses were
Materials and Methods
performed using SPSS version 19.0 for Windows (SPSS Inc.,
This was a randomized controlled trial at a single perinatal Chicago, IL).
care center conducted from 2013 to 2014 and was approved
by the Institutional Review Board at Saint Louis University.
Results
Normotensive women in the second or third trimester of
pregnancy who had symptoms of a primary headache (acute During the study period, 101 patients were screened. Eight
or tension type, as defined by the International Headache patients declined enrollment and 23 were ineligible for the
Society),18 which was not relieved by 650 to 1,000 mg of study. A total of 70 patients were enrolled, 35 women in the
acetaminophen, were eligible for the study. They were MAD group and 35 patients in the codeine group. One patient
approached for enrollment by research personnel after in the codeine group developed high blood pressure after
admission to the hospital or obstetric triage unit and voicing enrollment in the study and she underwent induction of
complaints of headache symptoms. Patients were excluded labor prior to the 6-hour time assessment; therefore, data
from the study if they were in the first trimester, less than were not collected for her beyond the 1-hour data collection
16 years of age, had received a headache treatment medica- point. Data were not available for two women in the MAD
tion other than acetaminophen in the previous 24 hours, had group and three women in the codeine group at the 6-hour
an allergy to one of the study medications, had abnormal assessment; therefore, 33 women were analyzed at the
intracranial anatomy or suspicion of a secondary cause of primary outcome in the MAD group and 32 women in the
headache, if their systolic blood pressure was 140 or codeine group. Three patients were lost to follow-up at the
diastolic blood pressure was 90, or were in active labor. 24-hour assessment, one in the MAD group and two in the
Patients were randomized to receive either the MAD codeine group; therefore, a total of 66 patients were available
regimen, consisting of 10 mg of IV metoclopramide and for analysis at the final 24-hour assessment, 34 in the MAD
25 mg of IV diphenhydramine (administered by IV push group and 32 in the codeine group (►Fig. 1).
over 2 minutes), or 30 mg of oral codeine. Randomization No differences in baseline demographics were noted
was in a 1:1 ratio by a predetermined computer-generated between the two groups (►Table 1). Mean initial headache
randomization sequence concealed in sequentially num- pain scores were not different between the MAD and the
bered opaque envelopes until patient enrollment in the codeine groups (7.6  1.7 vs. 7.4  1.5; p ¼ 0.61)
study. The study drug was repeated at 1 hour if the patient (►Table 2). Pain scores were lower for the MAD group at
did not perceive adequate pain relief with the first dose of each subsequent time point, although this difference was only
medication. If headache symptoms continued, patients were statistically significant at the 30-minute, 1-hour, and 12-hour
treated with additional nonstudy medications at the treating assessments (►Table 2, ►Fig. 2). We did not find a difference in
physician’s discretion. Subjective self-assessment of head- the primary outcome of at least a two-point difference in
ache severity on 11-point numeric scale of increasing pain numerical pain score at the 6-hour assessment. Patients
severity, with 0 representing no pain and 10 representing in the MAD group perceived relief sooner after treatment

American Journal of Perinatology


Metoclopramide and Diphenhydramine Childress et al.

Enrollment
Assessed for eligibility (n=101)

Excluded (n=31)
♦ Not meeting inclusion criteria (n=23)
♦ Declined to participate (n=8)
♦ Other reasons (n=0)

Randomized (n=70)

Allocation
Allocated to the MAD regimen (n=35) Allocated to the codeine regimen (n=35)
♦ Received allocated intervention (n=35) ♦ Received allocated intervention (n=35)
♦ Excluded (n=0)

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Follow-Up at 6
hours
Available for data collection (n=35) Available for data collection (n=34)
♦ Lost to follow up (n=0) ♦ Lost to follow up (n=0)
♦ Developed pre-eclampsia and was delivered
(n=1)

Analysis of
Primary Outcome
Analysed at 6 hours (n=35) Analysed at 6 hours (n=34)

Fig. 1 Consort flow diagram.

Table 1 Comparison of baseline characteristics of the population

MAD, n ¼ 35 Codeine, n ¼ 35 p-Value


Maternal age (years) 23 (21–25) 23.5 (21–27) 0.46
Gravidity 3 (1–4) 3 (2–4) 0.28
Parity 1 (0–2) 1 (1–2) 0.19
Gestational age (weeks) 31.9 (25.7–34.6) 28.4 (19.1–32.9) 0.29
Race
African-American 28 (80%) 25 (71.4%) 0.49
Caucasian 7 (20%) 10 (28.6%)
Obesity 15 (42.9%) 14 (40%) 1.00
History of prior migraines 4 (11.4%) 5 (14.3%) 1.00
History of prior headaches (any type) 21 (60%) 14 (42.9%) 0.19

Abbreviation: MAD, metoclopramide and diphenhydramine.


Note: Data are reported as medians (with interquartile ranges) or n (%). Groups did not differ significantly in any characteristic.

American Journal of Perinatology


Metoclopramide and Diphenhydramine Childress et al.

Table 2 Comparison of headache regimens

MAD, n ¼ 35 Codeine, n ¼ 35 p-Value


a
Median headache pain score
0 min 7.6 (7, 8.2) 7.4 (6.9, 7.9) 0.61
30 min 3 (2.1, 4) 5.8 (5, 6.6) <0.001
1h 2.2 (1.4, 3) 4.1 (3, 5.1) <0.01
6 hb 1.8 (0.8, 2.8) 2.5 (1.6, 3.5) 0.14
c
12 h 1.3 (0.4, 2.2) 2.7 (1.6, 3.7) <0.05
d
24 h 2.1 (1.1, 3.1) 2.9 (1.6, 4.2) 0.52
Time to perceived relief (minutes) 20 (5–30) 35 (22.5–60) <0.01
Received a second dose of study medication 3 (8.6%) 8 (23.5%) 0.17
Received nonstudy headache medication 7 (20%) 12 (34.3%) 0.28

Abbreviation: MAD, metoclopramide and diphenhydramine.


Note: Data are reported as means and standard deviations or n (%).
a
Headache pain scores were self-reported on an 11-point numeric scale of increasing pain severity from 0 (none) to 10 (severe).
b
Data are reported for 33 women in the MAD group and 32 women in the codeine group, with data available for assessment at 6 hours.

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c
Data are reported for 33 women in the MAD group and 31 women in the codeine group, with data available for assessment at 12 hours.
d
Data are reported for 34 women in the MAD group and 32 women in the codeine group, with data available for assessment at 24 hours.

than those in the codeine group (20.2  13.4 vs. did not reach statistical significance (38.2 vs. 59.4%;
62.4  62.2 minutes; p < 0.001; ►Table 2). A significant p ¼ 0.14). There was no difference between the two groups
interaction effect between group and time was found in the number of patients who experienced side effects from
(p < 0.05), indicating that the pattern of change in pain scores the study medication. Reported side effects were minor and
differed significantly between the MAD and codeine groups, included fatigue, dizziness, agitation, nausea, and IV site
with the MAD group experiencing a faster decrease in pain pain.
scores than the codeine group.
At the 24-hour final assessment, more patients in the
Discussion
MAD group reported that the first dose of study medication
worked (94.1 vs. 68.8%; p < 0.05; ►Table 3) and that they Treatment with IV MAD provided headache relief in preg-
had full relief of headache within 24 hours (76.5 vs. 37.5%, nant women with acute headaches not relieved by acetami-
p < 0.01). Fewer patients who received treatment with MAD nophen. Patients reported shorter times to perceived
reported recurrence of headache by 24 hours, although this headache relief than with codeine. Pain scores were lower

10.0
9.0
Mean headache pain score

8.0
7.0
6.0
*
5.0 Codeine
*
4.0 MAD
*
3.0
2.0
1.0
0.0
0 6 12 18 24

Time aer treatment (hours)


* =p <0.01
ǂData are presented as means with 95% confidence intervals

Fig. 2 Comparison of headache pain scores to the primary outcome of the 6-hour assessment.

American Journal of Perinatology


Metoclopramide and Diphenhydramine Childress et al.

Table 3 Comparison of subjective outcomes at the 24-hour assessment

MAD, n ¼ 34 Codeine, n ¼ 32 p-Value


Reported first dose of study medication 32 (94.1%) 22 (68.8%) <0.05
relieved headache
Reported relief after receiving a second dose of 3 (100%) 4 (57.1%) 0.48
study medicationa
Reported full relief of headache with study 26 (76.5%) 12 (37.5%) <0.01
medication at 24 h
Recurrence of headache at 24 h 13 (38.2%) 19 (59.4%) 0.14
Experienced any side effects 15 (44.1%) 10 (31.3%) 0.41

Abbreviation: MAD, metoclopramide and diphenhydramine.


Note: Data are reported as n (%).
a
Reported for the 10 women who required a second dose of study medication for unrelieved headache after the first dose of study medication; three
patients in the MAD group and seven patients in the codeine group received a second dose of study medication.

at all time points assessed, although this only reached sta- treatment option because it has a good safety profile in
tistical significance at 30 minutes, 1 hour, and 12 hours. Both pregnancy and is frequently used in pregnant patients for

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medication regimens achieved at least a two-point decrease the treatment of nausea and vomiting. IV metoclopramide
in pain score at 6 hours, but no statistical difference between has been shown to be effective in the treatment of acute
groups was seen in pain score at the 6-hour assessment. migraines when compared with sumatriptan,22,24 hydro-
Many of the secondary outcomes, however, including sub- morphone,25 prochlorperazine,23 and ketorolac.26 Its use
jective assessments at the 24-hour time point, indicated that should be considered as early therapy in the treatment of
the MAD regimen was superior to codeine. More patients acute migraines.
experienced full headache relief and less headache recur- Our study has important strengths and several limita-
rence with the MAD regimen. Furthermore, fewer patients in tions. It is a randomized, controlled trial of a sizeable number
the MAD group required treatment with a second dose of of pregnant participants. Our study is the first to specifically
study medication. study an alternative pharmacological treatment for acute
When compared with codeine, treatment with the MAD headaches in pregnancy when acetaminophen has failed. As
regimen provided faster pain relief. More patients had lower very little is published regarding effective treatments of
pain scores at the 30-minute assessment. This effect may be headache in pregnancy, our findings are a valuable
due to the IV administration of the medication. This study contribution.
took place in inpatient and triage settings within the hospi- The mechanism of action whereby MAD works to achieve
tal, making IV administration feasible. While placement of an headache relief is unknown. Both dopamine and serotonin
IV catheter does have its disadvantages, including increased have been implicated in the pathogenesis of acute headaches
cost and potential side effects, benefits such as shorter triage and migraines.27 Metoclopramide is a dopamine antagonist
and hospital admission times, and decreased need for addi- and also possesses weak serotonin-antagonistic activity. It is
tional medication gained by faster pain relief, may justify use possible that through these antagonistic properties, meto-
of IV catheters and lessen overall health care costs. Providing clopramide alters the inflammatory state of acute migraines.
treatment by an IV route also has advantages such as avoid- It is also likely that the antiemetic properties of metoclo-
ing oral medication intolerance in patients who may already pramide contribute to its effectiveness, as many patients
have nausea associated with headache. Furthermore, IV with acute migraines may have associated nausea. Diphen-
catheters are often already part of management in patients hydramine is often given with metoclopramide to prevent
receiving inpatient and emergency care treatment. possible akathisia reactions that can be associated with
Little evidence currently exists regarding the pharmaco- metoclopramide and for its sedating and potentially syner-
logical treatment of headache in pregnancy. Guidelines from gistic properties when used in combination.
the American Academy of Neurology and the European One of the limitations of our study is that codeine was
Federation of Neurological Societies on the treatment of used as standard for comparison to the MAD regimen. This
acute headaches and migraines suggest treatment with was because of poor patient enrollment with an earlier study
nonsteroidal anti-inflammatory drugs, other analgesics, design comparing MAD to placebo. Codeine was chosen for
triptans, ergot alkaloids, and antiemetics as preferred thera- comparison because narcotics are often used as second-line
pies, and note that pregnancy constitutes a special popula- therapy in emergency department settings.28,29 We were
tion, but do not specifically give recommendations for the also unable to blind patients or physicians due to the route of
treatment of headaches in pregnant patients.6–8 Therefore, medication administration and requirements by our Institu-
medications known to be safe in pregnancy and proven to be tional Review Board that patients in the codeine group would
effective in the treatment of headaches in nonpregnant not receive an IV catheter unless required for other aspects of
patients are generally used. Metoclopramide is an appealing their management. Our study population was also limited to

American Journal of Perinatology


Metoclopramide and Diphenhydramine Childress et al.

patients who were seeking care in a hospital setting at a assessment of migraine pharmacotherapies. Headache 2015;55
tertiary care center. The median age of patients was 23 years, (01):3–20
and the majority of them were African-American. Patients in 10 Gilmore B, Michael M. Treatment of acute migraine headache. Am
Fam Physician 2011;83(03):271–280
the first trimester and those with elevated blood pressures
11 Callan JE, Kostic MA, Bachrach EA, Rieg TS. Prochlorperazine vs.
were excluded. These factors may decrease overall general- promethazine for headache treatment in the emergency depart-
izability of the results. ment: a randomized controlled trial. J Emerg Med 2008;35(03):
Although MAD was superior to codeine in many of the 247–253
secondary outcomes studied, we did not find a difference in the 12 Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine
vs intravenous metoclopramide in acute migraine headache. Acad
primary outcome of at least a two point difference in numerical
Emerg Med 1995;2(07):597–602
pain scores at the 6-hour assessment. Patients who received
13 Bachur RG, Monuteaux MC, Neuman MI. A comparison of acute
MAD reported lower scores at all time points, but these treatment regimens for migraine in the emergency department.
differences were only statistically significant at 30 minutes, Pediatrics 2015;135(02):232–238
1 hour, and 12 hours. It is possible that our study was under- 14 Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclo-
powered to find statistically significant differences at all time pramide in the treatment of migraine headache. Ann Emerg Med
1993;22(02):191–195
points. Still, the two groups had similar scores, showing that
15 Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH.
they are at least similar in effectiveness. We also used a dose of Parenteral metoclopramide for acute migraine: meta-analysis of
10 mg of metoclopramide. Different dosing regimens have randomised controlled trials. BMJ 2004;329(7479):1369–1373
been used in studies in nonpregnant patients, with the only 16 Salazar G, Fragoso M, Vergez L, Sergio P, Cuello D. Metoclopramide
randomized controlled trial finding no difference between as an analgesic in severe migraine attacks: an open, single-blind,

Downloaded by: University College London. Copyrighted material.


10 mg, 20 mg, or 40 mg given intravenously for acute head- parallel control study. Recent Patents CNS Drug Discov 2011;6
(02):141–145
aches.30 It is possible that due to the altered physiology of
17 Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A.
pregnancy, 10 mg may not be the optimal dose. Increasing the The safety of metoclopramide use in the first trimester of preg-
dose to 20 mg may have potential benefits in a pregnant nancy. N Engl J Med 2009;360(24):2528–2535
population and remains to be studied. 18 Headache Classification Committee of the International Head-
In conclusion, our study demonstrates that treatment ache S. The International Classification of Headache Disorders,
3rd edition. Cephalalgia 2013;33:629–808
with IV MAD is an effective alternative in the treatment of
19 Todd KH, Funk JP. The minimum clinically important difference in
acute headache in pregnancy when acetaminophen alone
physician-assigned visual analog pain scores. Acad Emerg Med
has failed. Further prospective studies of the pharmacologic 1996;3(02):142–146
treatment of headaches in pregnancy are needed. 20 Kwong WJ, Pathak DS. Validation of the eleven-point pain scale in
the measurement of migraine headache pain. Cephalalgia 2007;
Funding 27(04):336–342
21 Kelly AM. Does the clinically significant difference in visual analog
None.
scale pain scores vary with gender, age, or cause of pain? Acad
Emerg Med 1998;5(11):1086–1090
Conflict of Interest 22 Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide
None. vs sumatriptan for the emergency department treatment of
migraines. Neurology 2005;64(03):463–468
23 Friedman BW, Esses D, Solorzano C, et al. A randomized controlled
References trial of prochlorperazine versus metoclopramide for treatment of
1 Digre KB. Headaches during pregnancy. Clin Obstet Gynecol 2013; acute migraine. Ann Emerg Med 2008;52(04):399–406
56(02):317–329 24 Talabi S, Masoumi B, Azizkhani R, Esmailian M. Metoclopramide
2 Pearce CF, Hansen WF. Headache and neurological disease in versus sumatriptan for treatment of migraine headache: a ran-
pregnancy. Clin Obstet Gynecol 2012;55(03):810–828 domized clinical trial. J Res Med Sci 2013;18(08):695–698
3 Macgregor EA. Headache in pregnancy. Continuum (Minneap 25 Griffith JD, Mycyk MB, Kyriacou DN. Metoclopramide versus
Minn) 2014;20(1 Neurology of Pregnancy):128–147 hydromorphone for the emergency department treatment of
4 MacGregor EA. Migraine in pregnancy and lactation. Neurol Sci migraine headache. J Pain 2008;9(01):88–94
2014;35(Suppl (Suppl 1):61–64 26 Friedman BW, Adewunmi V, Campbell C, et al. A randomized
5 Williams SH, Kehr HA. An update in the treatment of neurologic trial of intravenous ketorolac versus intravenous metoclopra-
disorders during pregnancy–focus on migraines and seizures. mide plus diphenhydramine for tension-type and all nonmi-
J Pharm Pract 2012;25(03):341–351 graine, noncluster recurrent headaches. Ann Emerg Med 2013;
6 Silberstein SD. Practice parameter: evidence-based guidelines for 62(04):311–318
migraine headache (an evidence-based review): report of the 27 Agosti RM. 5HT1F- and 5HT7-receptor agonists for the treatment
Quality Standards Subcommittee of the American Academy of of migraines. CNS Neurol Disord Drug Targets 2007;6(04):
Neurology. Neurology 2000;55(06):754–762 235–237
7 Evers S, Afra J, Frese A, et al; European Federation of Neurological 28 Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 3:
Societies. EFNS guideline on the drug treatment of migraine–revised opioids, NSAIDs, steroids, and post-discharge medications. Head-
report of an EFNS task force. Eur J Neurol 2009;16(09):968–981 ache 2012;52(03):467–482
8 Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoe- 29 Colman I, Rothney A, Wright SC, Zilkalns B, Rowe BH. Use of
nen J; EFNS. EFNS guideline on the treatment of tension-type narcotic analgesics in the emergency department treatment of
headache - report of an EFNS task force. Eur J Neurol 2010;17(11): migraine headache. Neurology 2004;62(10):1695–1700
1318–1325 30 Friedman BW, Mulvey L, Esses D, et al. Metoclopramide for acute
9 Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine: a dose-finding randomized clinical trial. Ann Emerg
migraine in adults: the American Headache Society evidence Med 2011;57(05):475–482

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