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,
Gynecology, and Women’s Health, Saint Louis University School of
Medicine, St. Louis, Missouri
Am J Perinatol
Address for correspondence Katherine M. Scolari Childress, MD,
Division of Maternal-Fetal Medicine, Department of Obstetrics,
Gynecology, and Women’s Health, Saint Louis University School of
Medicine, 6420 Clayton Road, Suite 2800, St. Louis, MO 63117
(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
to occur in more than 20% of patients.1,2 Pharmacological
treatment can be challenging with little evidence-based treat-
ment and most recommendations based on studies in non-
pregnant patients, involving medications that are felt to be safe
during pregnancy. Generally, acetaminophen is first-line med-
ication in the treatment of headaches in pregnancy, as it is felt
to be generally safe, is low in cost, and has few side effects.3–9
Second-line treatment when acetaminophen fails is more
controversial. Opiates, nonsteroidal anti-inflammatory drugs,
and triptans are used; however, concern exists regarding the
safety of these medications during pregnancy. Opiates also
pose potential for abuse, maternal dependence, and neonatal
withdrawal. Thus, common second-line agents may be
avoided, leaving limited options in the treatment of headache
during pregnancy.1–4,10
Some antiemetics, often in combination with antihista-
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.
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Metoclopramide and Diphenhydramine Childress et al.
in addition to their antinausea effects, and several rando-
mized controlled trials have shown their effectiveness as
headache treatment medications in nonpregnant
patients.11–13 Metoclopramide has been shown to be effec-
tive in the treatment of headaches in emergency department
settings.14–16 It is widely used in the treatment of nausea and
vomiting of pregnancy and data support its safety even in the
first trimester of pregnancy.14–17 Diphenhydramine is often
combined with metoclopramide for its sedating properties
and to prevent akathisia reactions. Both medications are low
in cost, are widely available, and considered safe in preg-
nancy. Although they have shown promise in the treatment
of headaches in nonpregnant patients, their effectiveness in
the treatment of headaches has not been studied in a
pregnant population.
The objective of our study was to investigate whether
treatment with a combination of intravenous (IV) metoclo-
pramide and diphenhydramine (MAD) effectively relieves
headache in pregnant patients when acetaminophen alone
is ineffective, using codeine as the standard for comparison.
We hypothesized that treatment with MAD would be as
effective as codeine for the relief of headaches in a pregnant
population.
Materials and Methods
This was a randomized controlled trial at a single perinatal
care center conducted from 2013 to 2014 and was approved
by the Institutional Review Board at Saint Louis University.
Normotensive women in the second or third trimester of
pregnancy who had symptoms of a primary headache (acute
or tension type, as defined by the International Headache
Society),18 which was not relieved by 650 to 1,000 mg of
acetaminophen, were eligible for the study. They were
approached for enrollment by research personnel after
admission to the hospital or obstetric triage unit and voicing
complaints of headache symptoms. Patients were excluded
from the study if they were in the first trimester, less than
16 years of age, had received a headache treatment medica-
tion other than acetaminophen in the previous 24 hours, had
an allergy to one of the study medications, had abnormal
intracranial anatomy or suspicion of a secondary cause of
headache, if their systolic blood pressure was 140 or
diastolic blood pressure was 90, or were in active labor.
Patients were randomized to receive either the MAD
regimen, consisting of 10 mg of IV metoclopramide and
25 mg of IV diphenhydramine (administered by IV push
over 2 minutes), or 30 mg of oral codeine. Randomization
was in a 1:1 ratio by a predetermined computer-generated
randomization sequence concealed in sequentially num-
bered opaque envelopes until patient enrollment in the
study. The study drug was repeated at 1 hour if the patient
did not perceive adequate pain relief with the first dose of
medication. If headache symptoms continued, patients were
treated with additional nonstudy medications at the treating
physician’s discretion. Subjective self-assessment of head-
ache severity on 11-point numeric scale of increasing pain
severity, with 0 representing no pain and 10 representing
American Journal of Perinatology
severe pain, was used to determine medication effectiveness
over a 24-hour period (at baseline, 30 minutes, 1 hour,
6 hours, 12 hours, and 24 hours) after administration of
the first dose of study medication. Patients were asked a
series of questions regarding their experience at the 24-hour
assessment. The primary outcome was a reduction in pain
score by at least two points 6 hours after medication admin-
istration.19–21 Secondary outcomes were differences in
headache scores at the other time assessments, whether
patients required additional doses of the study medication or
another nonstudy drug and whether patients experienced
headache recurrence, side effects, and other subjective
assessments of patient experience.
A sample size calculation of 35 patients in each group was
based on an estimated reduction in headache pain score by at
least two points, with an α of 0.05 and a power of 80%, which
is similar to estimates reported in prior studies in nonpreg-
nant patients and felt to be a clinically significant
decrease.19–23 Statistical analyses were performed using
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chi-square test and Fisher’s exact test for categorical vari-
ables, and independent Student’s t-test and Mann–Whitney
U test for continuous variables, as appropriate. Mixed models
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
performed using SPSS version 19.0 for Windows (SPSS Inc.,
Chicago, IL).
Results
During the study period, 101 patients were screened. Eight
patients declined enrollment and 23 were ineligible for the
study. A total of 70 patients were enrolled, 35 women in the
MAD group and 35 patients in the codeine group. One patient
in the codeine group developed high blood pressure after
enrollment in the study and she underwent induction of
labor prior to the 6-hour time assessment; therefore, data
were not collected for her beyond the 1-hour data collection
point. Data were not available for two women in the MAD
group and three women in the codeine group at the 6-hour
assessment; therefore, 33 women were analyzed at the
primary outcome in the MAD group and 32 women in the
codeine group. Three patients were lost to follow-up at the
24-hour assessment, one in the MAD group and two in the
codeine group; therefore, a total of 66 patients were available
for analysis at the final 24-hour assessment, 34 in the MAD
group and 32 in the codeine group (►Fig. 1).
No differences in baseline demographics were noted
between the two groups (►Table 1). Mean initial headache
pain scores were not different between the MAD and the
codeine groups (7.6
1.7 vs. 7.4
1.5; p ¼ 0.61)
(►Table 2). Pain scores were lower for the MAD group at
each subsequent time point, although this difference was only
statistically significant at the 30-minute, 1-hour, and 12-hour
assessments (►Table 2, ►Fig. 2). We did not find a difference in
the primary outcome of at least a two-point difference in
numerical pain score at the 6-hour assessment. Patients
in the MAD group perceived relief sooner after treatment
 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.
62.4
62.2 minutes; p < 0.001; ►Table 2). A significant
interaction effect between group and time was found
(p < 0.05), indicating that the pattern of change in pain scores
differed significantly between the MAD and codeine groups,
with the MAD group experiencing a faster decrease in pain
scores than the codeine group.
At the 24-hour final assessment, more patients in the
MAD group reported that the first dose of study medication
worked (94.1 vs. 68.8%; p < 0.05; ►Table 3) and that they
had full relief of headache within 24 hours (76.5 vs. 37.5%,
p < 0.01). Fewer patients who received treatment with MAD
reported recurrence of headache by 24 hours, although this
did not reach statistical significance (38.2 vs. 59.4%;
p ¼ 0.14). There was no difference between the two groups
in the number of patients who experienced side effects from
the study medication. Reported side effects were minor and
included fatigue, dizziness, agitation, nausea, and IV site
pain.
Discussion
Treatment with IV MAD provided headache relief in preg-
nant women with acute headaches not relieved by acetami-
nophen. Patients reported shorter times to perceived
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


Table 3 Comparison of subjective outcomes at the 24-hour assessment
Reported first dose of study medication
relieved headache
Reported relief after receiving a second dose of
study medicationa
Reported full relief of headache with study
medication at 24 h
Recurrence of headache at 24 h
Experienced any side effects
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-
tistical significance at 30 minutes, 1 hour, and 12 hours. Both
medication regimens achieved at least a two-point decrease
in pain score at 6 hours, but no statistical difference between
groups was seen in pain score at the 6-hour assessment.
Many of the secondary outcomes, however, including sub-
jective assessments at the 24-hour time point, indicated that
the MAD regimen was superior to codeine. More patients
experienced full headache relief and less headache recur-
rence with the MAD regimen. Furthermore, fewer patients in
the MAD group required treatment with a second dose of
study medication.
When compared with codeine, treatment with the MAD
regimen provided faster pain relief. More patients had lower
pain scores at the 30-minute assessment. This effect may be
due to the IV administration of the medication. This study
took place in inpatient and triage settings within the hospi-
tal, making IV administration feasible. While placement of an
IV catheter does have its disadvantages, including increased
cost and potential side effects, benefits such as shorter triage
and hospital admission times, and decreased need for addi-
tional medication gained by faster pain relief, may justify use
of IV catheters and lessen overall health care costs. Providing
treatment by an IV route also has advantages such as avoid-
ing oral medication intolerance in patients who may already
have nausea associated with headache. Furthermore, IV
catheters are often already part of management in patients
receiving inpatient and emergency care treatment.
Little evidence currently exists regarding the pharmaco-
logical treatment of headache in pregnancy. Guidelines from
the American Academy of Neurology and the European
Federation of Neurological Societies on the treatment of
acute headaches and migraines suggest treatment with
nonsteroidal anti-inflammatory drugs, other analgesics,
triptans, ergot alkaloids, and antiemetics as preferred thera-
pies, and note that pregnancy constitutes a special popula-
tion, but do not specifically give recommendations for the
treatment of headaches in pregnant patients.6–8 Therefore,
medications known to be safe in pregnancy and proven to be
effective in the treatment of headaches in nonpregnant
patients are generally used. Metoclopramide is an appealing
Metoclopramide and Diphenhydramine Childress et al.
MAD, n ¼ 34 Codeine, n ¼ 32 p-Value
32 (94.1%) 22 (68.8%) <0.05
3 (100%) 4 (57.1%) 0.48
26 (76.5%) 12 (37.5%) <0.01
13 (38.2%) 19 (59.4%) 0.14
15 (44.1%) 10 (31.3%) 0.41
treatment option because it has a good safety profile in
pregnancy and is frequently used in pregnant patients for
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the treatment of nausea and vomiting. IV metoclopramide
has been shown to be effective in the treatment of acute
migraines when compared with sumatriptan,22,24 hydro-
morphone,25 prochlorperazine,23 and ketorolac.26 Its use
should be considered as early therapy in the treatment of
acute migraines.
Our study has important strengths and several limita-
tions. It is a randomized, controlled trial of a sizeable number
of pregnant participants. Our study is the first to specifically
study an alternative pharmacological treatment for acute
headaches in pregnancy when acetaminophen has failed. As
very little is published regarding effective treatments of
headache in pregnancy, our findings are a valuable
contribution.
The mechanism of action whereby MAD works to achieve
headache relief is unknown. Both dopamine and serotonin
have been implicated in the pathogenesis of acute headaches
and migraines.27 Metoclopramide is a dopamine antagonist
and also possesses weak serotonin-antagonistic activity. It is
possible that through these antagonistic properties, meto-
clopramide alters the inflammatory state of acute migraines.
It is also likely that the antiemetic properties of metoclo-
pramide contribute to its effectiveness, as many patients
with acute migraines may have associated nausea. Diphen-
hydramine is often given with metoclopramide to prevent
possible akathisia reactions that can be associated with
metoclopramide and for its sedating and potentially syner-
gistic properties when used in combination.
One of the limitations of our study is that codeine was
used as standard for comparison to the MAD regimen. This
was because of poor patient enrollment with an earlier study
design comparing MAD to placebo. Codeine was chosen for
comparison because narcotics are often used as second-line
therapy in emergency department settings.28,29 We were
also unable to blind patients or physicians due to the route of
medication administration and requirements by our Institu-
tional Review Board that patients in the codeine group would
not receive an IV catheter unless required for other aspects of
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
tertiary care center. The median age of patients was 23 years,
and the majority of them were African-American. Patients in
the first trimester and those with elevated blood pressures
were excluded. These factors may decrease overall general-
izability of the results.
Although MAD was superior to codeine in many of the
secondary outcomes studied, we did not find a difference in the
primary outcome of at least a two point difference in numerical
pain scores at the 6-hour assessment. Patients who received
MAD reported lower scores at all time points, but these
differences were only statistically significant at 30 minutes,
1 hour, and 12 hours. It is possible that our study was under-
powered to find statistically significant differences at all time
points. Still, the two groups had similar scores, showing that
they are at least similar in effectiveness. We also used a dose of
10 mg of metoclopramide. Different dosing regimens have
been used in studies in nonpregnant patients, with the only
randomized controlled trial finding no difference between
10 mg, 20 mg, or 40 mg given intravenously for acute head-
aches.30 It is possible that due to the altered physiology of
pregnancy, 10 mg may not be the optimal dose. Increasing the
dose to 20 mg may have potential benefits in a pregnant
population and remains to be studied.
In conclusion, our study demonstrates that treatment
with IV MAD is an effective alternative in the treatment of
acute headache in pregnancy when acetaminophen alone
has failed. Further prospective studies of the pharmacologic
treatment of headaches in pregnancy are needed.
Funding
None.
Conflict of Interest
None.
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