The Clinic Analysis of Diclofenac Suppository for Oocyte Retrieval Analgesia in IVF-ET Cycles

doi:10.4236/ijcm.2013.48062

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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.

Email: [email protected]

Received June 3rd, 2013; revised June 23rd, 2013; accepted July 11th, 2013

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).

REFERENCES

[1] N. F. Vlahos, I. Giannakikou, A. Vlachos and N. Vitora-

tos, “Analgesia and Anesthesia for Assisted Reproductive

Technologies,” International Journal of Gynecology &

Obstetrics, Vol. 105, No. 3, 2009, pp. 201-205.

doi:10.1016/j.ijgo.2009.01.017

[2] M. Vosoughin, S. Mohammadi and A. Dabbagh, “Intra-

venous Ketamine Compared with Diclofenac Suppository

in Suppressing Acute Postoperative Pain in Women Un-

dergoing Gynecologic Laparoscopy,” Journal of Anesthe-

sia, Vol. 26, No. 5, 2012, pp. 732-737.

doi:10.1007/s00540-012-1399-1

[3] S. Mitra, P. Khandelwal and A. Sehgal, “Diclofenac-Tra-

madol vs. Diclofenac-Acetaminophen Combinations for

Pain Relief after Caesarean Section,” Acta Anaesthesi-

ologica Scandinavica, Vol. 56, No. 6, 2012, pp. 706-711.

doi:10.1111/j.1399-6576.2012.02663.x

[4] J. F. Standing, D. Tibboel, R. Korpela and K. T. Olkkola,

“Diclofenac Pharmacokinetic Meta-Analysis and Dose

Recommendations for Surgical Pain in Children Aged 1 -

12 Years,” Pediatric Anesthesia, Vol. 21, No. 3, 2011, pp.

316-324. doi:10.1111/j.1460-9592.2010.03509.x

[5] C. Kailasam, L. P. Hunt, I. Ryder, I. Bhakri and U. D.

Gordon, “Safety and Effectiveness of Diclofenac Sodium

in Assisted Reproduction Treatment: A Randomized Pro-

spective Double-Blind Study,” Reproductive BioMedicine

Online, Vol. 16, No. 5, 2008, pp. 724-729.

doi:10.1016/S1472-6483(10)60488-9

[6] V. Akande, A. Garas and D. Cahill, “The Effect of Di-

clofenac and Paracetamol on Pregnancy and Implantation

Rates in Infertile Women Undergoing IVF Treatment,”

Journal of Obstetrics and Gynaecology, Vol. 26, No. 8,

2006, pp. 785-787. doi:10.1080/01443610600984578

[7] J. F. Standing, K. Ooi, S. Keady, R. F. Howa rd, I. Savage

and I. C. Wong, “Prospective Observational Study of

Adverse Drug Reactions to Diclofenac in Children,”

British Journal of Clinical Pharmacology, Vol. 68, No. 2,

2009, pp. 243-251.

doi:10.1111/j.1365-2125.2009.03447.x

[8] L. C. Hamilton, J. A. Mitchell, A. M. Tomlinson and T. D.

Warner, “Synergy between Cyclo-Oxygenase-2 Induction

and Arachidic Acid Supply in Vivo: Consequences for

Nonsteroidal Antiinflammatory Drug Efficacy,” FASEB

Journal, Vol. 13, No. 2, 1999, pp. 245-251.

[9] H. Achache, A. Tsafrir, D. Prus, R. Reich and A. Revel,

“Defective Endometrial Prostaglandin Synthesis Identi-

fied in Patients with Repeated Implantation Failure Un-

dergoing in Vitro Fertilization,” Fertility and Sterility,

Vol. 94, No. 4, 2010, pp. 1271-1278.

doi:10.1016/j.fertnstert.2009.07.1668

[10] A. Bokhari and B. J. Pollard, “Anaesthesia for Assisted

Conception: A Survey of UK Practice,” European Jour-

nal of Anaesthesiology, Vol. 16, No. 4, 1999, pp. 225-

230.

[11] W. Wilhel m, M. E. Hammade h, P. F. White, T. Georg, R.

Fleser and A. Biedler, “General Anesthesia versus Moni-

tored Anesthesia Care with Remifentanil for Assisted Re-

productive Technologies: Effect on Pregnancy Rate,”

Journal of Clinical Anesthesia, Vol. 14, No. 1, 2002, pp.

1-5. doi:10.1016/S0952-8180(01)00331-2

[12] S. P. Boyers, G. Lavy , J. B. Russell and A. H. DeCherney,

“A Paired Analysis of in Vitro Fertilization and Cleavage

Rates of First- versus Last-Recovered Preovulatory Hu-

man Oocytes Exposed to Varying Intervals of 100% CO2

Pneumoperitoneum and General Anesthesia,” Fertility

and Sterility, Vol. 48, No. 6, 1987, pp. 969-974.

[13] P. O. Fiebai, A. A. Ogunmokun and R. A. Ajayi, “Ex-

perience with Conscious Sedation for Oocyte Retrieval in

Nigeria,” African Journal of Reproductive Health, Vol.

12, No. 1, 2008, pp. 30-34.