International Journal of Clinical Medicine, 2013, 4, 350-354
http://dx.doi.org/10.4236/ijcm.2013.48062 Published Online August 2013 (http://www.scirp.org/journal/ijcm)
The Clinic Analysis of Diclofenac Suppository for
Oocyte Retrieval Analgesia in IVF-ET Cycles
Yubin Li, Qingyun Mai, Tao Li, Yiping Zhong, Canquan Zhou
The Reproductive Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Received June 3rd, 2013; revised June 23rd, 2013; accepted July 11th, 2013
Copyright © 2013 Yubin Li et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Obje ctive: To study the effect of diclofenac suppository in oocyte retrieval of IVF-ET. Study Design: 1176 patients
with informed consents were enrolled into this prospective randomized controlled study. The setting was an IVF-ET
program at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. According to the analgesic drug
use, the patients were randomly divided into pethidine group (573 cases) and diclofenac suppository group (603 cases).
The data of vital signs, common adverse reactions, severe adverse events and pain degree in oocyte retrieval were col-
lected. The IVF-ET outcomes were also compared. Results: The post-operation pressure and pulse were lower in
pethidine gr oup than in diclofen ac supp o sitory gro up (both P < 0.001).Th e rest vital signs were not statistically different
(all P > 0.05). Common adverse reactions in diclofenac suppository group were relatively less (all P < 0.05). Pain de-
gree between the two groups was not statistically different (P = 0.304). IVF-ET outcomes were also not statistically
different (all P > 0.05). There were 3 cases serious abdominal bleeding with shock in the diclofenac suppository group.
Conclusion: Using diclofenac suppository in oocyte retrieval analgesic had a good effect. And there was no adverse
effect in the IVF-ET outcome. But we should pay close atten tion to the probability of serious abdominal bleeding.
Keywords: Diclofenac Suppository; IVF-ET; Oocyte Retrieva l; Analgesia
1. Introduction
With the vigorous development of assisted reproductive
technology, in vitro fertilization-embryo transfer (IVF-
ET) technique has gradually become the routine method
in current infertility treatment. Oocyte retrieval in IVF-
ET protocol is an invasive step, which is often mediated
by trans vag inal u ltras onogr aphy. The su rgeries often lead
to lower abdominal pain. And sometimes it is even un-
bearable. In many IVF reproductive centers, pethidine is
chosen for analgesia in the operation. Other drugs such
as propofol, nitrous oxid e also achieved good r esults. But
the unknown influences of narcotic drugs on the oocytes
often limit the use of effective analgesic drugs. So the
pain in some patients has not been effectively alleviated
[1]. Diclofenac suppository had been efficiently used in
gynecological and obstetric operations [2,3]. Recently in
some IVF centers, it also was used in oocyte retrieval. In
order to learn more about the clinical efficacy and safety
of this drug in IVF treatment protocols, we carried out
this clinical analysis.
2. Materials and Methods
2.1. Clinical Characteristics
1176 patients undergoing IVF treatment in our hospital
from November 2011 to April 2012 were collected into
the study, which included conventional IVF-ET and in-
tracytoplasmic sperm injection (ICSI-ET). Before opera-
tions all patients signed informed consents. The study ob-
tained the approval from the ethics committee of The
First Affiliated Hospital of Sun Yat-sen University. Ova-
rian hyperstimulation protocols were conventional long
protocols and short protocols. The patients, aged from 22
to 42 years old, didn’t have any contraindications of oo-
cyte retrieval and using of pethidine, diazepam and di-
clofenac in accordance with the medication instructions.
They didn’t have vital organs dysfunction, and didn’t use
aspirin and other anti-clotting drugs. Bilateral ovarian re-
serves of all patients were good, and the total antral fo lli-
cles were more than 5. In accordance with the analgesic
drugs used before operations, the patients were randomly
divided into two groups: the observation group using

The Clinic Analysis of Diclofenac Suppository for Oocyte Retrieval Analgesia in IVF-ET Cycles 351
diclofenac suppository (603 cases) (Tongyao, Wuhan,
China), and the control group using pethidin (573 cases)
(Renfu, Yichang, China). The patients’ age, body mass
index (BMI), constituent ratios of ovarian hyper-stimu-
lation protocols and insemination methods were all not
statistically different compared between the two groups
(all P > 0.05).
2.2. Oocyte Retrieval and the Analgesic Drugs
Use
All patients undergoing oocyte retrievals were after ova-
rian hyperstimulation protocols. Before operations, the
patients were routin ely asked common p hysical cond itio n,
checked vital signs and identity information. Analgesic
drugs were used 10 - 15 minutes before oocyte retrieval
by our nurses randomly. The patients in control group
were intramuscular injected 50 mg pethidine for analge-
sia. And in observation group the patien ts inserted 50 mg
diclofenac suppositories into rectum. The doctors had
adequate oocyte retrieval experience. The operations were
guided by transvaginal ultrasonography using 16 G oo-
cyte-retrieval needles un der negative pressure (110 - 120
mmHg) on both ovaries. We must avoid the puncture
needles injuring blood vessels and passing through uter-
uses and bladders. During the operations, we recorded
the pain response, vital signs and common adverse reac-
tions. The common adverse reactions included dizziness,
palpitations, nausea, vomiting and cold sweat, etc. The
nurses recorded the patients’ blood pressure, pulses, oxy-
gen saturation when finishing aspirating one side of
ovary. And then the doctors continued to the other sides.
When finishing oocyte retrieval, we should observe whe-
ther there was apparent abdominal active hemorrhage by
ultrasound carefully. Also we must pay attention to the
bleeding of vaginal wall. Finally we recorded the post-
operative blood pressure, pulse, blood oxygen saturation.
Oocyte retrieval time of all cases was within 15 minutes.
2.3. Recording Severe Adverse Events
Abdominal massive hemorrhage with shock (which needed
surgery to stop bleeding), cardiovascular and cerebro-
vascular accidents affecting the lives were recorded.
2.4. Evaluation Criteria of Pain Degree in Oocyte
Retrieval
In according to the patients’ pain response in oocyte re-
trieval, it was divided into 4 grades. Grade 0: no pain, a
little discomfort; Grade 1: mild pain, do not feel abdo-
minal pain when distracted, only feel brief tingling when
the needle through vaginal wall; Grade 2: moderate pain,
feel abdominal pain throughout the procedure with mild
autonomic nervous dysfunction even when distracted, but
patients still can tolerate; Grade 3: severe pain through-
out the procedure with significant autonomic nervous
dysfunction. Patients cannot tolerate and demand strongly
to stop or suspend the surgeries. The patients’ pain de-
grees were judged and recorded by a specific person
from our study staff by single-blind method.
2.5. Comparison of IVF-ET Outcomes
The numbers of oocytes, fertilization rates, high-quality
embryo rates, biochemical pregnancy rates were com-
pared between the two groups. The biochemical preg-
nancy was defined as confirming blood β-HCG positive
14 days after embryo transfer.
2.6. Statistical Analysis
The Variance Analysis and χ2 test were performed for
statistical analysis by using the SPSS 11.0. A P value less
than 0.05 was considered statistically significant.
3. Results
3.1. Comparison of the Perioperation Vital Signs
In Table 1, it shows that the blood pressure, pulse and
oxygen saturation are not statistically different before the
oocyte retrieval operation between the two groups (P >
0.05). During the operation, those differences were not
significant yet (P > 0.05). But blood pressure and pulse
in diclofenac suppository group reduced when compared
with those in pethidin e group (P < 0.001) after operation,
except for oxygen saturation.
3.2. Common Adverse Reactions during the
Operations (Table 2)
The incidences of nausea, vomiting and dizziness be-
tween the two groups were significantly different. The
incidences in the diclofenac suppository group were rela-
tive lower (P < 0.001). No particular symptom rate be-
tween the two groups were also significantly different ( P
< 0.001).
3.3. Severe Adverse Events
There were no death, emergency su rgery and other major
adverse events in the pethidine group during the six
months of clinical study. In the diclofenac suppository
group, no death has occurred. But there were three cases
of abdominal bleeding with shock in it, which were re-
quired emergency laparotomies. The total blood loss was
about 900 ml, 1000 ml and 2000 ml respectively. The
shock reasons were all ovarian bleeding. The time inter-
vals between oocyte-retrievals and the sudden abdominal
pain with shock were 8 hours, 20 hours and 9 hours re-
spectively. No acute serious shock happened just after

The Clinic Analysis of Diclofenac Suppository for Oocyte Retrieval Analgesia in IVF-ET Cycles
352
Table 1. Comparison of the perioperation vital signs between the two groups.
Pethidine group Diclofenac group t Value P Value
Cases 573 603
Preoperation 114.3 ± 19.2 112.9 ± 16.7 0.97 0.33
Blood pressure (mmHg) Intraoperation 110.7 ± 22.7 109.4 ± 17.1 1.11 0.25
Postoperation 101. 2 ± 17.7 111.5 ± 13.1 11.38 <0.001
Preoperation 85.4 ± 8.9 85.9 ± 10.9 0.86 0.39
Pulse (beat/min) Intraoperation 84.9 ± 16.3 85.1 ± 11.8 0.24 0.83
Postoperation 79.2 ± 13.2 83.4 ± 10.1 6.15 <0.001
Preoperation 98.6 ± 0.9 98.5 ± 1.0 1.79 0.07
Oxygen saturation (%) Intraoperation 98.5 ± 1.0 98.6 ± 1.1 0.24 0.09
Postoperation 98.6 ± 0.9 98.7 ± 1.1 1.70 0.07
Table 2. Comparison of perioperation common adverse reactions (case).
Case Nausea vomiting Dizziness No particular symptom
Pethidine group 573 161(a) 23(b) 48(c) 371(d)
Diclofenac group 603 73 6 21 519
Compared with the study group, (a)χ2 = 47.14, P < 0.001; (b)χ2 = 11.13, P = 0. 001; (c)χ2 = 12.74, P < 0.001; (d)χ2 = 72.58, P < 0.001.
operations.
3.4. Comparison of the Pain Degree during the
Oocyte Retrieval (Table 3)
The pain degree was not statistically different between
the two groups ( P = 0.304). Most of the patients suffered
mild or moderate pain during the operations.
3.5. Comparison of IVF-ET Outcomes
The differences of average oocyte, normal fertilization
rate, number of available embryos rate and biochemical
pregnancy rate were not statistically significant between
the two groups (P > 0.05) (Table 4).
4. Discussion
In IVF-ET protocols, transvaginal puncture and oocyte
aspiration guided by B-ultrasonic are invasive steps. Oo-
cyte retrieval often brings fear and pain to some patients.
Therefore the proper use of analgesic drugs is necessary.
And it must ensure that the drug using in oocyte retrieval
have no potential impact on the oocytes, embryos, and
the future babies.
Pethidine analg esia is one of the most traditional an al-
gesia methods in the IVF-ET oocyte retrieval, which is
often used as a control of new analgesia methods. In cli-
nic, pethidine is usually used together with diazepam in
order to release the anxiety and fear of the patients. Dic-
Table 3. Comparison of the degree of pain between the two
groups (case).
CaseGrade 0 Grade 1 Grade 2Grade 3
Pethidine group573 42 376 148 7
Diclofenac
group(a) 603 54 412 132 5
(a)Compared between the two groups: χ2 = 3.629, P = 0.304.
lofenac is an effective, opiate-sparing analgesic for acute
pain, which is commonly used in pediatric surgical units
[4]. So we speculated diclofenac should also be safe for
IVF-ET. The main ingredient and its chemical name of
diclofenac sodium suppository is 2-[(2,6-dichlorophenyl)
amino]-Sodium Phenylacetate, a derivative of isobutyl
diclofenac sodium. Its analgesic, anti-inflammatory and
antipyretic effects are 2 to 2.5 times stronger than indo-
methacin, and 26 to 50 times than aspirin. Kailasam and
Akande reported that using diclofenac suppository in
IVF-ET had a good effect without obvious adverse ef-
fects [5,6]. The analgesic, anti-inflammatory effects of
diclofenac work by inhibiting cyclooxygenase and re-
ducing prostaglandin generation. And it also can inhibit
the lipoxygenase, which reduces the production of leu-
kotriene and bradykinin. In our study we used 50 mg dic-
lofenac suppository for analgesia and got a good effect.
The drug has no adverse impact on the IVF-ET outcome,
as the reports of Kailasam and Akande. But in both of

The Clinic Analysis of Diclofenac Suppository for Oocyte Retrieval Analgesia in IVF-ET Cycles 353
Table 4. Comparison of the IVF-ET outcomes.
Case Oocyte (n) Normal fertilization rate (%) Available embryo rate (%) Pregnancy rate (%)
Pethidine group 573 6992 76.83 (5372/69 92 ) 45.92 (3211/69 92 ) 43.28 (248/573)
Diclofenac group 603 7831 74.01 (5796/78 31 ) 44.86 (3513/78 31 ) 42.12 (254/603)
that two studies [5,6], diclofenac suppository was ad-
ministered rectally immediately after the oocyte retrieval.
In our study, diclofenac suppository was administered
before the operatio n. And the outcome still i ndicated that
the drug has no obvious adverse effects on IVF-ET out-
comes even used before operation. The incidence of com-
mon adverse reactions induced by diclofenac suppository
is lower than by pethidine. The probable reason is that
the pethidine is a central analgesic, when intramuscular
injecting it can cause autonomic n ervous system disorder
symptoms in some patients, such as dizziness, headache,
nausea, vomiting, and so on. But diclofenac suppository
is rectal administration, which is a local medication. So
diclofenac suppository has slighter systemic symptom
and seldom induce nervous and gastrointestinal distur-
bance. In addition, the result showed that the blood pres-
sure and pulse were higher and recovered faster in di-
clofenac suppository group comparing with pethidine
group. It indicates that diclofenac suppository group pa-
tients have more equability vital sign s and less complica-
tion during oocyte retrieval. This requires further basic
research to confirm. And the rectal administration by pa-
tients themselves can save the injection time of nurses
and reduce the anesthetic management pressure. The
above all may be the advantage of diclofenac supposi-
tory.
A study of Standing showed that the incidence of se-
rious adverse reaction by using diclofenac suppository
was <0.8 % [7]. In ou r study, 3 cases of sev ere abdominal
bleeding happened after using diclofenac suppository,
which needed emergency operations. And they took place
more than 8 hours after the oocyte retrievals. Such cases
in the control group did not appear, or so far rare. Re-
viewing the using of pethidine for oocyte retrieval anal-
gesia in the near 5 years in our center, there was only one
cases of severe abdominal bleeding. But she was a plate-
let dysfunction patient. Her pelvic vascular plexus was
injured by punctu re needle du ring the oper ation requir ing
emergency surgery to stop bleeding. Although it was still
difficult to draw a conclusion because of the small cases
in our study, it must pay attention to the relevance be-
tween diclofenac suppository and severe abdominal bl e ed -
ing after oocyte retrieval. The diclofenac and aspirin are
both non-steroidal anti-inflammatory and analgesic drugs.
From the aspect of pharmacology, these drugs can inhibit
the generation of prostaglandins, histamine and brady-
kinin with larger doses. But with small doses they can in-
hibit prostaglandi n cy cl ooxy g e nase (C OX), r e duce throm-
boxane A2 (TXA2) generation and inhibit platelet ag-
gregation, which cause a bleeding tendency [8]. In this
study, three cases of acute bleeding occurred after a long
time of the oocyte retrieval, but not just after the punc-
ture operations. Commonly when vascular were injured
by the punctures, the bleeding should often occur imme-
diately in normal coagulation patients. We speculate that
the effective drug dose in rectum may decrease with time
after treatment, and it lead to an anti-platelet effect and
cause bleeding tendency. Reviewing the relative litera-
ture, we d id not find the report about the severe abdomi-
nal bleeding after using diclofenac suppository for anal-
gesic in oocyte retrieval yet.
In this study, we have not yet found an adverse effect
on success rate in IVF-ET protocols with diclofenac sup-
pository. However, some studies had found that pros-
taglandin cyclooxygenases (COXs), including COX-1
and COX-2，play an important role in ovulation , implan-
tation, and endometrial decidualization [9]. It may have
an effect on the reproductive system in principle as di-
clofenac can inhibit the COXs. In th is study, IVF-ET out-
comes were similar between the two groups. The reason
may be the short duration of drug action. But this was de-
served further researches.
Reviewing the literature, we found that conscious se-
dation, propofol, nitrous oxide and acupuncture are used
in oocyte retrieval analgesia of IVF-ET, which have dif-
ferent advantages and disadvantages [1,10]. Intravenous
anesthesia is often considered the most comfortable.
However, the studies of Wilhelm [11] and Boyers [12]
had found adverse effects of intravenous anesthetics on
the ooctyes and embryos. For this reason, Intravenous
anesthesia is not the most popular method of anesthesia
used in IVF protocol [13].
5. Conclusion
In summary, diclofenac suppository and pethidine both
have good effects in oocyte retrieval analgesic. But the
former has the advantages of ease use, relatively stable
vital signs and fewer adverse reactions during operation.
However, it must pay attention to the possibility of caus-
ing late-onset abdominal bleeding. A variety of oocyte
retrieval analgesia methods are carried out, but different
reproductive cen ters should choose the most suitable me-
thod based on di fferent patien t s and cent ers.

The Clinic Analysis of Diclofenac Suppository for Oocyte Retrieval Analgesia in IVF-ET Cycles
354
6. Acknowledgements
The work was supported by The National Natural Sci-
ence Foundation of China (grant no. 81100470 and
81270750), The Young Teacher Training Project of Sun
Yat-sen University, China (Grant No. 12ykpy24) and Na-
tural Science Foundation of Guangdong Province, China
(Grant No. S2012010009390).
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