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PROMETHAZINE COMPARED WITH

METOCLOPRAMIDE FOR HYPEREMESIS


GRAVIDARUM
A RANDOMIZED CONTROLLED TRIAL

Presenter Dr Surya Prasad rimal, Junior resident


Moderator Dr Pritha Basnet, Assistant professor

OBSTETRICS & GYNECOLOGY


VOL. 115, NO. 5, MAY 2010
Peng Chiong Tan, Pwint Phyu Khine, Narayanan
Vallikkannu, and Siti Zawiah Omar

Location: Department of Obstetrics and Gynecology,


University of Malaya, Lembah Pantai, Kuala Lumpur,
Malaysia

Duration

: From November 25, 2008,


to August 14, 2009

Subjects: A total of 73 and 76 women, randomized to


metoclopramide and promethazine, respectively

OBJECTIVES

To compare the effects of promethazine with


metoclopramide for hyperemesis gravidarum.

OBJECTIVES

VERSUS

INTRODUCTION
Hyperemesis gravidarum is practically defined as
pernicious vomiting in pregnancy that requires
hospitalization.
It typically is associated with dehydration, electrolyte
disturbances, and starvation with consequent weight
loss.
It affects 0.3% to 2.3% of the pregnant population,
whereas nausea and vomiting of pregnancy is far
more common, affecting up to 85% of pregnant women.

The

mainstays of therapy: rehydration,


antiemetics, and enhancement of coping
mechanisms.

ACOG

2004 guidelines
dimenhydrinate,metoclopramide,or
promethazine as first-line antiemetic.

Hyperemesis Gravidarum
When the joy of creating life turns
into a struggle for survival and hope
I Wish . . .
I wish that I had never tried to get
pregnant
I wish that in a few months I would
be able to hold my baby

METOCLOPRAMIDE

increases

the movements
or contractions of the muscles
prokinetic

Side Effects
does not cause as many side effects as many other
medicines used to prevent nausea and vomiting.
May include:
Sleepiness or confusion.
Twitching or muscle spasms.
Decreased blood pressure (hypotension).
Rapid or uncontrolled movements of lips and tongue.
Contra indications:
narrow-angle glaucoma, prostate disease, severe low
blood pressure, or rapid, irregular heartbeats.

PROMETHAZINE
Promethazine,

a phenothiazine derivative,
Acts primarily as a strong antagonist of
the H1 receptor (antihistamine) and a
moderate mACh receptor antagonist
(anticholinergic and also has weak to
moderate affinity for the 5-HT2A,[11] 5HT2C,[11] D2,[12][13] and 1-adrenergic
receptors,[14] where it acts as an antagonist
at all sites, as well.

SIDE EFFECTS
Tardive

dyskinesia
Confusion in the elderly
Drowsiness, dizziness, fatigue, more
rarely vertigo Dry mouth
Constipation
Chest discomfort/pressure (typically in
cases when patient is already taking
medication for high blood pressure)

METHODOLOGY
Women

hospitalized for the first time in their


current pregnancies with presumed hyperemesis
gravidarum were approached
Informed written consent.
Ethical approval

INCLUSION CRITERIA

Clinical hyperemesis gravidarum with dehydration


and detectable ketonuria by urine dipstick at a
gestation of 16 weeks or less.

EXCLUSION CRITERIA
multiple

gestation,
Established nonviable pregnancy,
preexisting medical condition that can cause
nausea and vomiting (eg, culture proven
symptomatic urinary tract infection or dengue fever),
gastrointestinal causes of vomiting (eg,
gastroenteritis),
medical causes of vomiting (eg, diabetic
ketoacidosis),
known allergy to metoclopramide /promethazine

PRIMARY OUTCOME
well-being visual numerical rating scale score and
frequency of vomiting in the first 24 hours

SECONDARY OUTCOMES
visual numerical rating scale scores for nausea at
enrolment and at 8, 16, and 24 hours;
adverse symptoms profile;
ketonuria status at the end of the 24-hour main study
period;
treatment curtailment during the main study period;
total doses of intravenous antiemetic needed during
hospitalization;
admission- to-discharge interval; and
time needed for intravenous rehydration

ASSIGNMENT TO TREATMENT GROUP


Participants

were recruited by providers as they


were admitted to the gynecology ward.
After obtaining consent, participants were
assigned randomly by the sequential opening of
numbered, sealed, opaque envelopes stating
Drug A or Drug B.
These numbered envelopes were prepared by
an author (P.P.K.) in random blocks of four or
eight using a computer-generated randomization
sequence

Study

drugs were placed in identical vials.


Each vial contained a colorless 5-mL solution,
and the vial was labeled as A or B to effect
double blinding of drug allocation.
The solutions contained either 10 mg of
metoclopramide or 25 mg of promethazine.
The contents of vials A and B was swapped
between metoclopramide and promethazine
periodically to strengthen blinding; that is, the
study drugs were in vials labeled differently at
different stages of the study.
This was not revealed to providers.

Antiemetic

therapy as randomly allocated was


administered by slow injection into an indwelling
intravenous catheter over 1 to 2 minutes by
providers just after randomization and 8, 16,
and 24 hours later for a full course of four doses
as per trial protocol.
Participants were instructed to chart vomiting
episodes as they occurred during the 24-hour
study period and to mark the nausea visual
numerical rating scale (10 points, high score
denoting more severe nausea) before initial
administration of the study drug and 8, 16, and
24 hours after administration of the study drug.

Also

at 24 hours, participants were


asked to mark their perceived wellbeing over the study period with a 10point visual numerical rating scale
(higher score greater well-being) and
to answer a preset questionnaire
(yes or no answers) on symptoms
experienced during the study
period.

At

the conclusion of the 24-hour main


study period, the allocated
intravenous study antiemetic could be
stopped or continued as allocated or
open-label treatment (either
intravenous or oral) instituted at the
providers discretion.

SAMPLE SIZE ESTIMATION


Based

on the hypothesis that


metoclopramide will produce an overall
well-being visual numerical rating scale
score at 24 hours that is 1 unit better than
that produced by promethazine (using a
10-point visual numerical rating scale),
assuming a visual numerical rating scale
standard deviation of 2, 0.05, and 80%
power.
Sixty-four women were required in each
arm.

Visual

numerical rating scale score might not


be normal and that the Mann-Whitney U test
might have to be applied instead of the
Students t test, so, 10% increase to the
enrollment.
For 10% drop-out rate, it was planned to
enroll a total of 158 women to perform a
suitably powered study.

STATISTICAL ANALYSIS
SPSS 16
Students t test.
Two-by-two categorical data sets were analyzed
with the Fisher exact test and larger categorical
data sets with the 2 test; ordinal data and non
normally distributed continuous data were
analyzed with the Mann-Whitney U test

Numbers needed to treat were generated using


GraphPad QuickCalc (GraphPad Software Inc., La
Jolla, CA).
P.05 was considered significant

RESULTS

Primary outcome
not significantly different.
Median vomiting frequency one (range 026) compared
with two (range 026) (P.81) and

Well-being visual numerical rating scale score 8 (range


110) compared with 7 (range 210) (P.24) for the
metoclopramide and promethazine arms, respectively

SECONDARY OUTCOME
nausea

visual numerical rating scale


very similar at each time point when
assessed individually.

Length of hospital stay, persistence of ketonuria at 24


hours, overall treatment curtailment, duration of
intravenous rehydration, and total doses of intravenous
antiemetic given during hospitalization were not
different between the trial arms.

SECONDARY OUTCOME.

Questionnaire on symptoms at the end of the 24-hour


main study period, the 3 Ds

drowsiness (58.6% compared with 83.6%,


P.001, number needed to treat to benefit
[NNTb] 5),
dizziness (34.3% compared with 71.2%, P.001,
NNTb 3), and
dystonia (5.7% compared with 19.2%, P.02,
NNTb 8) were reported less frequently for
metoclopramide than for promethazine

CONT.

Difficulty in sleeping, dry mouth, diarrhea,


headache, palpitations, and skin rash were reported
in similar proportions across the trial arms.

DISCUSSION
A trial directly comparing promethazine with
metoclopramide for hyperemesis gravidarum has
not been done.
However, a three-armed trial of placebo compared
with metoclopramide compared with promethazine
(with the first dose of pethidine) for labor analgesia
has shown that metoclopramide and promethazine
are equally effective in reducing the incidence of
nausea and vomiting but that the sedative effect
was more persistent in the promethazine group.
These findings are similar the data of this study .

Metoclopramide

has a desirable effect of


prokinetic action but this study indicate
that esophageal reflux is probably not an
important contributor to symptoms in
hyperemesis gravidarum
September 16, 2009, the U.S. FDA
warned of potential local tissue
damage, including gangrene, from
promethazine injection and mandated a
black box warning on the drug insert.

LIMITATIONS OF THE STUDY

The primary outcomes were over a 24-hour time scale


only

recruited on the basis of presumed hyperemesis


gravidarum before investigation results were available.
Later discovery of trial criteria infringements resulted in
postrandomization exclusion of 10 out of 159 (6.3%)
women

small number of participants whose data were


incomplete

CONCLUSION
Intravenous

metoclopramide or promethazine for


hospitalized hyperemesis gravidarum patients
produced similar therapeutic effects.
Metoclopramide resulted in fewer reported side
effects and treatment curtailment owing to
adverse events.
Intravenous metoclopramide is preferred over
intravenous promethazine for the treatment of
hyperemesis gravidarum.

Patient

had metabolic and


biochemical characteristics
comparable with other women in
reported studies of hyperemesis
gravidarum. Hence, findings can
be generalized.

REFERENCES
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CONT.
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CONT..
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CONT..
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Metoclopramide
(n73)

Promethazine
(n76)

Weight (kg)

54.3 9.1

54.210.5

.95

Body mass index


(kg/m2)

23.0 3.5

22.5 4.2

.45

Coexisting medical
condition

4 (5.5)

6 (7.9)

.75

1+

16 (21.9)

16 (21.1)

2+

15 (20.5)

12 (15.8)

3+

32 (43.8)

43 (56.6)

4+

10 (13.7)

5 (6.6)

At recruitment
Ketonuria(dipstick)

Metoclopramide
(n73)

Promethazine
(n76)

Nausea score*

5 (2.757)

5 (1.57) .85

.85

Serum sodium
(mmol/L)

134 4

134 2

.78

Serum potassium
(mmol/L)

3.9 0.5

3.9 0.5

.86

Hematocrit

0.39 0.04

0.39 0.03

.57

Pulse

84 13

82 12

.37

Systolic blood
pressure
(mmHg)

114 11

117 12

.15

Diastolic blood
pressure
(mmHg)

69 10

71 11

.24

Primary outcomes

Metoclopramide
(n73)

Promethazine
(n76)

Vomiting
episodes
(n144)

1 (05)

2 (03)

.81

Well-being
VNRS
(n142)

8 (610)

7 (5.259)

.24

7.62.2

7.12.3

.24

Primary
outcomes

Relative
Risk
(95% CI)

NNTb*
(95% CI)

Metoclopramide
(n73)

Promethazine
(n76)

At recruitment (n143)

5 (2.757

5 (1.57)

.85

8 h (n143)

4 (1.55

4 (1.756)

.54

16 h (n137)

3 (15)

3 (15)

.80

24 h (n126)

2 (15)

2 (14)

.99

Secondary outcomes

Nausea score

Metoclopramid Promethazine
e
(n76)
(n73)
Hospital stay (d) (n149)

1.8 (1.52.5)

1.7 (1.52.4)

Nil

54 (75.0))

61 (80.3)

1+

6 (8.3)

7 (9.2)

2+

9 (12.5)

5 (6.6)

3+

3 (4.2)

3 (3.9)

Ketonuria (dipstick) at the end of


the
study period (n148)

Metoclopramide
(n73)

Promethazine
(n76)

Intravenous
rehydration (h)
(n147)

42 (3359)

39 (3348.75)

.23

Full study drug course


not completed

4/73 (5.5)

9/76 (11.8)

.25

Full study drug course


not completed
owing to adverse
events

0/73 (0)

7/76 (9.2)

.014

4 (44.75)

.98

Intravenous antiemetic 4 (44)


doses

Metoclopramide
(n73)

Promethazine
(n76)

Relative Risk
(95% CI)

NNTb*
(95% CI)

Felt drowsy

41/70 (58.6)

61/73 (83.6)

.001

0.7 (95% CI 0.60.9)

5 (39)

Unable to sleep

12/70 (17.1)

16/73 (21.9)

.53

0.8 (0.41.5)

Had dry mouth

28/70 (40.0)

32/73 (43.8)

.74

0.9 (0.61.3)

Felt dizzy

24/70 (34.3)

52/73 (71.2)

<.001

0.5 (0.30.7)

Had diarrhea

4/70 (5.7)

3/73 (4.1)

.71

1.4 (0.36.0)

Had headache

17/70 (24.3)

22/73 (30.2)

.46

0.8 (0.51.4)

Experienced
palpitations

7/70 (10)

12/73 (16.4)

.33

0.6 (0.31.5)

Involuntary muscle
movement
(dystonia

4/70 (5.7)

14 (19.2)

.02

0.3 (0.10.9)

Noticed skin rash

4/70 (5.7)

3/73 (4.1)

.71

1.4 (0.36.0)

Symptoms profile
by questionnaire
(n143)

3 (25)

8 (434)

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