Accepted Manuscript

Comparison of non-steroidal anti-inflammatory drugs and misoprostol for pain reliefduring and after hysterosalpingography: A prospective, randomized controlled trial

Hikmet Hassa, Tufan Oge, Yunus Aydin, Derya Burkankulu

PII: S1553-4650(14)00193-9

DOI: 10.1016/j.jmig.2014.02.014

Reference: JMIG 2264

To appear in: The Journal of Minimally Invasive Gynecology

Received Date: 10 January 2014

Revised Date: 26 February 2014

Accepted Date: 27 February 2014

Please cite this article as: Hassa H, Oge T, Aydin Y, Burkankulu D, Comparison of non-steroidalanti-inflammatory drugs and misoprostol for pain relief during and after hysterosalpingography: Aprospective, randomized controlled trial, The Journal of Minimally Invasive Gynecology (2014), doi:10.1016/j.jmig.2014.02.014.

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Comparison of non-steroidal anti-inflammatory drugs and misoprostol for pain 1

relief during and after hysterosalpingography: A prospective, randomized 2

controlled trial 3

4

Hikmet Hassa1, Tufan Oge 2, Yunus Aydin2, Derya Burkankulu³ 5

6

1 Professor in Obstetrics and Gynecology, Eskisehir Osmangazi University School of 7

Medicine, Department of Obstetrics and Gynecology, Eskisehir, Turkey 8

2 Assistant Professor in Obstetrics and Gynecology, Eskisehir Osmangazi University 9

School of Medicine, Department of Obstetrics and Gynecology, Eskisehir, Turkey 10

³ Resident Doctor in Obstetrics and Gynecology, Eskisehir Osmangazi University 11

School of Medicine, Department of Obstetrics and Gynecology, Eskisehir, Turkey 12

13

Financial support: The authors report no financial support. 14

Conflict of interest: The authors have no conflict of interest. 15

16

Corresponding Author: 17

Tufan OGE, MD, 18

Eskisehir Osmangazi University School of Medicine, 19

Department of Obstetrics and Gynecology, 20

Eskisehir, 26480, Turkey 21

e-mail address: tufanoge@gmail.com 22

phone number: +90 222 2392979/3100 23

24

25

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Comparison of non-steroidal anti-inflammatory drugs and misoprostol for pain 51

relief during and after hysterosalpingography: A prospective, randomized 52

controlled trial 53

Abstract 54

Study objective: To assess whether vaginal misoprostol or oral non-steroidal anti-55

inflammatory drugs (NSAIDs) reduce pain during and 30 min after 56

hysterosalpingography (HSG). 57

Design: Randomised prospective, controlled, parallel-group study (Canadian Task 58

Force Classification I) 59

Settings: University based teaching hospital. 60

Patients: One hundred and sixty eight women primarily infertile women who 61

underwent hysterosalpingography for the evaluation of infertility. 62

Interventions: Patients were randomly assigned to group I (200 micrograms of 63

misoprostol vaginally 6 hours before HSG), group II (50 mg diclofenac potassium per 64

orally 45-60 min before HSG) and group III (no medication). The primary outcome of 65

the study was to evaluate the severity of pain during and 30 minutes after the 66

procedure using a visual analog scale (VAS) ranging from 1 (very favorable) to 10 67

(very unfavorable). The secondary outcomes were to assess the rate of completion and 68

the vasovagal effects including nausea, vomiting, sweating weakness, syncope, 69

hypotension, and bradycardia. 70

Measurements and Main Results: There was no statistically significant difference 71

in the median (25-75%) VAS pain scores between women administered vaginal 72

misoprostol [median, 6.7 cm (4.7-9)] and the control group [median, 6.7 cm (4.6-8.8)] 73

during the HSG. However, women in the NSAID group [median, 5.5 cm (3-7.6)] 74

reported less pain than those in the misoprostol group (p= .009) and the control group 75

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(p= .025) (Table 2, Figure 2). Thirty minutes after HSG, there was no significant 76

difference in the median VAS pain scores between patients who were administered 77

NSAIDs [median, 2.3 cm (1.4-4.2)] or misoprostol [median, 2.3 cm (1.2-4.4)] and the 78

control group [median, 2.2 cm (1.3-4.4)]. 79

Conclusions: This first randomized controlled trial indicates that there is no benefit in 80

terms of pain reduction with the use of misoprostol during HSG or 30 minutes after 81

the procedure. However, NSAIDs have a favorable outcome for pain relief during the 82

HSG procedure. 83

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Key words: hysterosalpingography; misoprostol; non-steroidal anti-inflammatory 85

drugs; visual analog scale 86

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Comparison of non-steroidal anti-inflammatory drugs and misoprostol for pain 101

relief during and after hysterosalpingography: A prospective, randomized 102

controlled trial 103

Introduction 104

Infertility is one of the most common health care problems in reproductive medicine. 105

Because it covers a heterogeneous group of patients, infertility work-ups require 106

additional attention to determine the etiology. Hysterosalpingography (HSG) is an 107

essential step for the evaluation of tubal patency and the uterus, and the NICE 108

guidelines recommend the use of HSG to screen for tubal occlusion in the absence of 109

comorbidities [1]. 110

Although HSG is a noninvasive procedure and does not require cervical dilatation or 111

anesthesia, patients may feel discomfort and lower abdominal pain during or after the 112

procedure due to cervical manipulation, uterine distention and peritoneal irritation. 113

The pain during this procedure has a negative impact on the patient’s adaptation to 114

treatment, and clinicians make an effort to overcome this unpleasant situation. In the 115

English literature, many studies have compared the effectiveness of different types of 116

pharmacological interventions, including non-opioid analgesics versus placebo [2, 3], 117

opioid analgesics versus non-opioid analgesics [4] and topical analgesics versus 118

placebo [5-8] as well as intracervical block [9] or the temperature of the contrast 119

media [10]. 120

Misoprostol is a prostaglandin E1 analog that is commonly used to treat postpartum 121

hemorrhage as well as in labor induction and to induce abortion and cervical ripening 122

prior to hysteroscopy [11, 13]. Misoprostol administration has been reported to be an 123

effective and safe method of cervical priming to facilitate the procedure without 124

anesthesia [14, 15]. Moreover, utilization of vaginal misoprostol to soften the cervix 125

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to facilitate HSG procedure was reported as a letter to the editor concluding that a 126

large study is needed to confirm the experience of misoprostol usefulness during HSG 127

[16]. 128

To the best of our knowledge, no prospective studies have evaluated the effects of 129

misoprostol on pain perception during HSG. We therefore hypothesized that cervical 130

priming with vaginal misoprostol can effectively reduce pain during HSG. To begin 131

testing this hypothesis, we prospectively evaluated the effect of misoprostol on pain 132

and compared misoprostol to NSAIDs (diclofenac potassium), which is one of the 133

most potent NSAIDs reviewed in the Cochrane Review of pain relief in 134

hysterosapingography [17] and a control group using a visual analog scale (VAS). 135

Materials and Methods: This was a randomized, prospective, controlled parallel-136

group study comparing the efficacy of vaginal misoprostol and NSAIDs on pain 137

perception during and after HSG in women with primarily infertilty. The study was 138

conducted in the Eskisehir Osmangazi University Department of Obstetrics and 139

Gynecology between 2011 and 2012 and was approved by the medical ethics 140

committee with the number 8055872/158. 141

Women who visited to our infertility department and underwent HSG for an infertility 142

work-up were enrolled in the study group. The exclusion criteria were as follows: 1) 143

contraindication to misoprostol- cardiovascular disease, hypertension, severe asthma, 144

glaucoma, renal failure, or allergy to prostaglandins; 2) contraindication to OH-145

cervical stenosis, active or recent cervical-endometrial infection, profuse vaginal 146

bleeding, known reproductive tract malignancy, pregnancy; 3) contraindications to 147

NSAIDs-previously reported adverse reaction, known hypersensitivity, known 148

gastroesophageal disease, genital bleeding; 4) other-history of cervical operation, 149

presence of acute pelvic inflammatory disease, use of analgesics during the study 150

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period. Eligible patients were informed and kindly invited to join the study by the 151

members of the research team. After signing the informed consent form, patients were 152

randomized into three groups using computer-generated random numbers, and the 153

surgeon performing the HSG was blinded to the randomization during the study 154

period. 155

Drugs were prescribed and/or applied by one member of the research team. Women in 156

the misoprostol and NSAID groups received 200 micrograms of misoprostol 157

(Cytotec®, ARIS, Turkey) vaginally 6 hours before and 50 mg of diclofenac 158

potassium (Cataflam®, Novartis, Turkey) per orally 45-60 min before the HSG 159

procedure, respectively. Patients who did not receive any drug were enrolled in the 160

control group. 161

Patients were in the follicular phase of their menstrual cycle and underwent HSG as 162

an outpatient operation. Procedures were performed in a lithotomic position on a 163

fluoroscopic table. A sterile speculum was inserted into the vagina. After the 164

visualization of the uterine cervix, a standard 3% povidone-iodine solution was used 165

for local cleaning. Then, the anterior or posterior cervical lip was grasped by a single-166

toothed tenaculum, and a Rubin HSG cannula was gently placed into the cervical 167

canal. The speculum was removed, and 15 mL of a water-soluble radio-opaque 168

solution (Ultravist® 300, Schering, Turkey) was used as a contrast medium and 169

injected slowly under spot fluoroscopy. At the end of the procedure, all instruments 170

were removed, and the patients were observed in the clinic for half an hour. 171

Patients were asked to record the severity of pain, which was the primary outcome of 172

the study, during and 30 minutes after the procedure using a VAS ranging from 1 173

(very favorable) to 10 (very unfavorable). The secondary outcomes were to assess the 174

rate of completion and the vasovagal effects including nausea, vomiting, sweating 175

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weakness, syncope, hypotension, and bradycardia. 176

The sample size was estimated according to the VAS scores of the patients as a 177

primary outcome. We assumed that the maximum mean difference among the groups 178

was 1.5 and that the standard deviation within each group was 2.5 on the basis of our 179

clinical experience [18] and earlier studies [5-7, 9, 10]. We applied a power analysis 180

for a one-way ANOVA and estimated that 55 patients would be needed in each group 181

to achieve 80% power with a type I error of 0.05. We predicted that no participants 182

would be lost to follow-up because the main outcome was observed during and after 183

the procedure. However, we decided to add 5-10% of the number of required patients 184

in the event that data were not used in the analysis. For this reason, a sample size of 185

60 participants was intended for each group. 186

We performed all statistical analyses with IBM Statistics-20.0 and Minitab 16.0. A 187

normal distribution of the continuous variables was evaluated by the Shapiro-Wilk 188

test. The Kruskal-Wallis test was used for non-normally distributed variables, which 189

were expressed as the median (25th – 75th percentiles). Categorical variables were 190

compared between groups using the chi-square test, and the frequencies and 191

percentiles were given. A p value less than 0.05 (p< .05) were accepted as statistically 192

significant. 193

Results: 194

During the study period, 266 women were evaluated at the infertility clinic for HSG, 195

and 180 primarily infertile women expressed interest in enrolling in the study. Twelve 196

women did not meet the eligibility criteria and were excluded from the study. Thus, 197

168 women were randomized to receive NSAIDs (n=57) (Group I) and misoprostol 198

(n=54) (Group II) before HSG. Fifty-seven patients were enrolled into the control 199

group (Group III). Twelve patients were lost after the randomization, and 156 patients 200

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received the allocated treatment (Figure 1). The median (25-75%) ages of the patients 201

were 30 (24.7-37) years, 28 (24-34) years, and 28 (24-36) years in the NSAID group, 202

misoprostol group, and control group, respectively. The baseline demographic and 203

clinical characteristics for each group are presented in Table 1. 204

There was no significant difference in patient age, BMI, duration of infertility, 205

operation time, or volume of contrast medium injected between the three groups. 206

The median pain scores during and at 30 minutes after the HSG were recorded as a 207

primary outcome using a 10-cm linear VAS and are shown in Table 2. There was no 208

statistically significant difference in the median (25-75%) VAS pain scores between 209

women administered vaginal misoprostol [median, 6.7 cm (4.7-9)] and the control 210

group [median, 6.7 cm (4.6-8.8)] during the HSG. However, women in the NSAID 211

group [median, 5.5 cm (3-7.6)] reported less pain than those in the misoprostol group 212

(p= .009) and the control group (p= .025) (Table 2, Figure 2). Thirty minutes after 213

HSG, there was no significant difference in the median VAS pain scores between 214

patients who were administered NSAIDs [median, 2.3 cm (1.4-4.2)] or misoprostol 215

[median, 2.3 cm (1.2-4.4)] and the control group [median, 2.2 cm (1.3-4.4)]. 216

Vasovagal effects including nausea, vomiting, sweating, weakness, syncope, 217

hypotension, and bradycardia were evaluated as a secondary outcome, and no 218

significant difference was detected in the number of women reporting these effects 219

between the groups (Table 2). 220

Discussion: 221

In the present study, we found no benefit to the use of misoprostol for pain relief in 222

women undergoing HSG when compared with the control group. However, the use of 223

NSAIDs had beneficial effects on pain perception during the procedure. Neither 224

NSAIDs nor misoprostol significantly reduced pain compared to the control group 30 225

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minutes after the procedure. 226

A major strength of the present study is the blinding of the observer to the study 227

groups and the acceptable power of the study. However, the study still has limitations 228

and involves inherent biases such as participant ascertainment biases. Although the 229

patients were unaware of the study protocol, lack of blinding of the subjects is a 230

limitation of the study and the patients allocated to the control group may have felt 231

disappointment and may have been less willing to report and/or have chosen to 232

exaggerate their pain perception during the study because we did not prefer placebo to 233

the control group. As vaginal misoprostol soften the cervix, it may be more helpful in 234

a subgroup of patients who need cervical manipulation [16]. This may be the 235

weakness of the study, but we did not predict the accumulation of those patients who 236

need cervical manipulation in any of the groups and similar to other literature, we did 237

not find that misoprostol decreased the pain in our patients [19]. Another important 238

limitation of the study is the measurement of patient pain intensity. We used a 10-cm 239

linear VAS to calculate the pain scores, which has established statistical validity and 240

reliability, pain is still a subjective symptom and may lead to measurement bias. 241

However, the measurement bias would be similar among all groups and may not 242

affect the final results of the study. Lastly, lack of placebo group is another limitation 243

of the study. According to the Cochrane’s data there is no benefit of analgesics versus 244

placebo however our results revealed that women in NSAID group reported less pain 245

than in the vaginal misoprostol and the control group [17,20]. Therefore, clinicians 246

should take our results cautiously on the basis of Cochrane’s review and the published 247

literature. 248

Misoprostol is widely used in cervical ripening prior to gynecological transcervical 249

procedures. Misoprostol in primarily used in transcervical procedures to increase the 250

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baseline cervical diameter and reduce pain during instrumentation. Although 251

misoprostol is widely used in patients who undergo office hysteroscopy, studies are 252

still conflicting as to whether the routine administration of misoprostol has beneficial 253

effects in premenopausal women [21, 22]. In a study by Moore et al. [23], pain 254

sources during HSG were described as cervical instrumentation, pain secondary to 255

uterine distension with contrast media, and pain due to peritoneal irritation as a result 256

of contrast spill into the peritoneal cavity. We hypothesized that cervical priming with 257

misoprostol may decrease the filling pressure of the uterus with contrast media and 258

decrease pain, but our results indicated that misoprostol did not affect the VAS 259

outcomes compared to the control group. 260

The use of NSAIDs is the method of choice for reducing the pain felt during HSG 261

[24, 25]. Opioid analgesics, non-opioid analgesics, and topical analgesics are also 262

efficacious for pain relief during HSG [3, 6]. Moreover, paracervical local anesthetic 263

injection is presented as a best method of pain control for women undergoing 264

hysteroscopy [26]. In the present study, oral NSAIDs significantly reduced VAS pain 265

scores when compared with patients who received misoprostol and the control group. 266

In addition, our study did not find any difference between the groups according to our 267

secondary outcomes, including nausea, vomiting, sweating weakness, syncope, 268

hypotension, and bradycardia. 269

To our knowledge, this is the first randomized controlled trial evaluating the efficacy 270

of misoprostol as a means of reducing pain during HSG. In conclusion, we were 271

unable to demonstrate any benefit in terms of pain reduction during HSG or 30 272

minutes after the procedure with the use of misoprostol. However, NSAIDs had a 273

favorable outcome for pain relief during HSG. Further studies are needed with 274

different timing and dosages of administration of vaginal misoprostol and placebo 275

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controlled randomized studies will better evaluate and compare the effects of drugs 276

which are used in this article.” 277

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Acknowledgement: Authors have no conflict of interest. 279

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3. Owens OM, Schiff I, Kaul AF, Cramer DC, Burt RA. Reduction of pain 309

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prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril 324

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cream as analgesia for hysterosalpingography: a prospective, randomized, 327

controlled, double blinded study. Hum Reprod 2007;22:1335-9. 328

9. Chauhan MB, Lakra P, Jyotsna D, Nanda S, Malhotra V. Pain relief during 329

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25. Gupta N, Ghosh B, Mittal S. Comparison of oral naproxen and intrauterine 376

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ACCEPTED MANUSCRIPTTable 1: Patient characteristics and pain scores of the groups

Control group

(n=55)

NSAID* group

(n=50)

Misoprostol group

(n=51)

P

Age, year 28 (24-36) 30 (24.75-37) 28 (24-34) 0.502

Body mass index (kg/m2) 24 (20.9-27) 23.5 (20.3-27.9) 24 (21.3-27) 0.841

Duration of infertility, (month) 36 (14-75) 33 (17-69) 37 (19-81) 0.916

History of endometriosis, n (%) 4 (7.2) 3 (6.1) 3 (5.8) 0.872

Total time of HSG, min 2.7±1.3 2.1±1.1 2.9±1.0 0.747

Volume of contrast infused, ml 11.3±3.9 12.1±4.2 11.9±3.8 0.876

Analgesic requirement after HSG** , n (%) 2 (3.6) 1 (2) 1 (1.9) 0.912

Vasovagal symptoms during HSG, n (%) 3 (5.4) 2 (4) 3 (5.8) 0.832

VAS*** , during HSG 6.7 (4.6-8.8) 5.5 (3.0-7.6) 6.7 (4.7-9.0) 0.019

VAS, 30 min after HSG 2.2 (1.3-4.3) 2.3 (1.4-4.2) 2.3 (1.2-4.4) 0.102

Data are expressed as Mean± Standard Deviation for normally distributed variables, median (25-75%) for non-normally

distributed variables and n (%) in others *NSAID: Nonsteroidal anti-inflammatory drug ** HSG: Hysterosalpingography *** VAS: Visual analog scale.

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Table 2: Comparison of pain scores in paired groups by using visual analog scale during

hysterosalpingography procedure

Groups Pain Scores P value

Control group vs. NSAID group 6.7 (4.6-8.8) vs. 5.5 (3.0-7.6) 0.025

Control group vs. Misoprostol group 6.7 (4.6-8.8) vs. 6.7 (4.7-9.0) 0.662

NSAID group vs. Misoprostol group 5.5 (3.0-7.6) vs. 6.7 (4.7-9.0) 0.009

Data are expressed as median (25-75%)

P-value <0.05 was considered statistically significant.

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Figure Legends 401

Figure 1. Patient flowchart 402

Figure 2. Boxplot view of median pain scores of groups during HSG procedure. 403

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Figure 1: Patient flowchart

Fol

low

up

n=50 Lost to follow up (n =0)

n=55 Lost to follow up (n =0)

Ana

lysi

s

Analyzed (n = 50) Excluded from analysis (n =0)

Analyzed (n = 55) Excluded from analysis (n =0)

Randomized (n = 168)

NSAID (n =54)

� Received allocated intervention (n = 50)

� Did not receive allocated intervention (n = 4)

Allo

cati

on

Assessed for eligibility (n = 180)

Excluded (n = 12) Pelvic pain (n=4) Pelvic inflammatory disease (n=4) Previous cervical operation (n = 1) Usage of analgesics (n = 1)

Enr

ollm

ent

Misoprostol (n =57)

� Received allocated intervention (n = 51)

� Did not receive allocated intervention (n = 6)

Control (n =57)

� Received allocated intervention (n = 55)

� Did not receive allocated intervention (n = 2)

n=51 Lost to follow up (n =0)

Analyzed (n = 51) Excluded from analysis (n =0)

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