Effect of cervical Lidocaine-Prilocaine cream on pain perception during cop-
per T380A intrauterine device insertion among parous women: a randomized
double-blind controlled trial

Ahmed M. Abbas, Mohamed S. Abdellah, Mohamed Khalaf, Mustafa

Bahloul, Noura H. Abdellah, Mohamed K. Ali, Ahmed M. Abdelmagied

PII: S0010-7824(16)30478-4
DOI: doi: 10.1016/j.contraception.2016.10.011
Reference: CON 8842

To appear in: Contraception

Received date: 11 August 2016

Revised date: 26 October 2016
Accepted date: 27 October 2016

Please cite this article as: Abbas Ahmed M., Abdellah Mohamed S., Khalaf Mohamed,
Bahloul Mustafa, Abdellah Noura H., Ali Mohamed K., Abdelmagied Ahmed M., Effect
of cervical Lidocaine-Prilocaine cream on pain perception during copper T380A intrauter-
ine device insertion among parous women: a randomized double-blind controlled trial,
Contraception (2016), doi: 10.1016/j.contraception.2016.10.011

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
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 ACCEPTED MANUSCRIPT

Effect of cervical Lidocaine-Prilocaine cream on pain perception during copper T380A

intrauterine device insertion among parous women: a randomized double-blind
controlled trial

Ahmed M. Abbas a*, Mohamed S. Abdellah a, Mohamed Khalaf a, Mustafa Bahloul a,

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Noura H. Abdellah b, Mohamed K. Ali a, Ahmed M. Abdelmagied a

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(a) MD., Department of Obstetrics & Gynecology, Faculty of Medicine. Assiut University, Assiut, Egypt.

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(b) MD., Department of Pharmaceuticals, Faculty of Pharmacy. Assiut University, Assiut, Egypt.

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* Corresponding author MA
Dr. Ahmed M. Abbas, MD
Department of Obstetrics and Gynecology,
Assiut University, Egypt
Women Health Hospital,
71511, Assiut Egypt
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Cellular: +20 10033851833

Tel: +20 88 2414616
Fax: +20 88 9202503
E-mail: bmr90@hotmail.com
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Trial registration: Clinicaltrials.gov NCT02658773.

Word counts: Abstract: 247 words, Manuscript: 2545 words.
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Abstract

Objective:

To investigate the analgesic effect of cervical lidocaine-prilocaine (LP) cream in

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alleviating pain during copper T380A intrauterine device (IUD) insertion among parous

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women.

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Study design:

We conducted a randomized, double-blind, placebo-controlled trial at Assiut Women’s

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Health Hospital, Egypt from October 2015 to April 2016 of parous women desiring
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copper IUD insertion. We randomized the subjects in a 1:1 ratio to LP cream or Placebo.

Seven minutes prior to IUD insertion, women received 2 mL of LP cream or placebo to

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the anterior cervical lip, followed by 2 mL placed in the cervical canal using a Q-tip

applicator. The study endpoint was the subjects’ self-reported pain using a 10-cm Visual
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Analogue Scale (VAS) during cervical tenaculum placement, sound insertion, IUD
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insertion, and 5 minutes post-procedure. We considered a 2 cm difference in VAS scores

between study groups as clinically significant. Also, the difference in the ease of
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insertion score using a 10-cm VAS with 0= very easy insertion, and 10= terribly difficult

insertion was assessed.

Results:

The study included 120 women (n=60 in each group). LP cream reduces the median VAS

pain scores during tenaculum placement (2 vs. 4), sound insertion (3 vs. 6), and IUD

insertion (3 vs. 6.5) with p=0.0001 at all steps. A lower ease of insertion score was also

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determined among LP women (2.5±0.98 vs. 4.5±2.7, p=0.001). Participants reported no

side effects.

Conclusions:

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Use of cervical LP cream prior to copper T380A IUD insertion may alleviate the IUD

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insertion pain among parous women.

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Implications:

Cervical lidocaine-prilocaine cream could be effective as an analgesic prior to copper

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T380A IUD insertion with no side effects. Further studies are needed to assess the
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women’s’ satisfaction from lying with a speculum in place for 7 minutes while waiting

for the cream to be effective.

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Key words:

Intrauterine device; lidocaine-prilocaine; contraception; pain relief; local anesthetic.

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1. Introduction:

Long-acting reversible contraception (LARC) methods are highly effective methods

for reduction of the unplanned pregnancy rate worldwide [1]. The intrauterine device

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(IUD) is a single procedure that provides reliable, effective and long term contraception

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for many women [2]. However, the insertion procedure can be associated with a

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troublesome degree of pain that prevent some women from choosing its use [3].

IUD insertion steps that can induce pain include application of the tenaculum to

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grasp the cervix; passing the sound for measuring the uterine length, introducing the
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IUD inserter tube; and release of the IUD inside the uterus [4]. Different interventions

have been described to decrease pain perception during IUD insertion with no
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agreement on an effective one [5]. Pre-insertion oral ibuprofen, diclofenac,

nitroprusside, local anesthetics as lidocaine and prostaglandins has been reported

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with variable degrees of success [4, 6-9].

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Local anesthetics have been extensively studied for a variety of different

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indications involving the genital mucosa, including 2% lidocaine gel, LP cream,

benzocaine 20% gel, cocaine spray and 2% mepivacaine gel [10].

Lidocaine-prilocaine (LP) cream is an oil/water emulsion in which the oil phase is a

eutectic mixture of two anesthetics; lidocaine 2.5% and prilocaine 2.5% in a ratio of 1:1

by weight [11]. After application of LP cream to female genital mucosa, it is rapidly

absorbed with an onset time of action 5 to 10 minutes [11]. The application of LP

cream on the cervix prior to office hysteroscopy [12], and hysterosalpingography (HSG)

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[13] studied before and was an effective local anesthetic before minor gynecological

procedures.

A recent Cochrane review (2015), entailed different interventions for pain relief

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with IUD insertion, included a single randomized controlled trial of 92 women found LP

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cream was superior to placebo [14]. They expressed the need for more trials to prove

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the efficacy of its use [5].

The current study aims to investigate the analgesic effect of lidocaine-prilocaine

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cream in alleviating pain during copper T380A IUD insertion among parous women.
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2. Materials and Methods:

The current study was a prospective, randomized, double-blind, placebo-

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controlled registered trial (NCT02658773), conducted in Assiut Women’s Health

Hospital, Egypt between the 1st of January 2016 and the 31st of May 2016. The Assiut
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University Medical Ethical Review Board approved the study.

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We clinically evaluated all women attended the Family Planning Clinic during the
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study period requesting an IUD insertion and invited them to participate in the study if

they had no contraindications for insertion in accordance with WHO eligibility criteria

[16]. We recruited parous women as IUD is not requested by nulliparas or outside the

context of marriage in Egypt. We included menstruating women, non-pregnant, aged

18-49 years old who did not receive any analgesics or misoprostol in the 24 hours prior

to insertion. We excluded women with any uterine abnormalities as congenital

anomalies, endometrial lesions, adenomyosis, fibroids, and allergy to lidocaine.

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All eligible participants included in the study signed a written informed consent

before participation. One of the study researchers approached all included women and

collected the baseline data. Then, he explained the standard 10-cm visual analog scale

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(VAS) to the participants for pain scoring [15]. The severity of pain was assessed with

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VAS (with 0= no pain and 10= worst imaginable pain). Each woman received a copper

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T380A IUD (ParaGard®T380A; Teva Pharmaceuticals USA, Inc. North Wales) for

insertion.

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We randomly assigned all participants in a 1:1 ratio into one of two groups:
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Lidocaine-prilocaine (LP group): women had LP anesthetic cream (Pridocaine®;

GLOBAL NAPI PHARMACEUTICALS (GNP), Egypt) placed into their cervix prior to
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insertion and Placebo group: women had an inert placebo cream created to be

identical in consistency, odour and color to the LP cream.

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A statistician, not otherwise involved in the study, prepared a computer generated

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random table and placed the allocation data in serially numbered sealed envelopes.
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Each envelope had a card noting the group identifier inside. A single pharmacist was

responsible for the manufacturing of the placebo cream and packaging of both

preparations into sterile tubes with labeling them as A and B. Only the Pharmacist

knew what was the medication in tube A and B, so neither the clinician nor the women

knew the type of the preparation. The clinician opened the envelopes according to the

order of attendance of women and used the tube A or B according to the card.

Four experienced gynecologists inserted the IUDs using the standard technique of

application prescribed by the manufacturer. Firstly, the clinician placed a plastic

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speculum into the vagina and cleansed the cervix with povidone iodine. Seven minutes

prior to IUD insertion, 2 mL of the study cream was placed on the anterior lip of the

cervix by a Q-tip applicator, followed by 2 mL introduced in the cervical canal up to the

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level of internal os. The woman stayed lying in bed with the speculum in place till

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completing the insertion procedure. After 7 minutes exposure to the cream, the

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clinician grasped the cervix with a tenaculum, and inserted the uterine sound for

measurement of the uterine length followed by IUD insertion. Immediate

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complications such as uterine perforation, failure of insertion, and vasovagal reaction
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were recorded.

A research assistant standing beside the woman asked her to rate the intensity of
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pain at four different points; during tenaculum placement, during sound insertion, at

time of IUD insertion and 5 minutes after the end of insertion using the same 10-point
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VAS with a different sheet of paper at every point. After the end of procedure, the
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clinician assessed the ease of IUD insertion using the ease of insertion score (ES). The
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ES is a graduated VAS-like scale from zero to 10; in which 10 means terribly difficult

insertion and zero means very easy insertion. Finally, the clinician asked all women

about the need for any additional analgesics at 15 minutes after completing the

procedure. Ibuprofen 400 mg was offered as an additional analgesic if needed. We

contacted the participants by telephone 24 hours later to report any side effects of the

medications encountered as burning sensation, skin reactions or allergy.

The primary outcome was the difference in pain VAS scores during IUD insertion.

The secondary outcomes included the difference in pain scores during tenaculum

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application, insertion of sound and five minutes after insertion, the ease of IUD

insertion, the number of women who need analgesics after insertion, and the side

effects of the medication.

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Sample size was calculated using the Open Epi software program, version 2.3.1.

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Most of previous studies consider a median VAS pain score with IUD insertion 5 cm in

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the placebo group [5]. We estimated that a 2 cm difference in the VAS pain score to be

clinically significant. Using two sided chi-square (χ2) test with α of 0.05, a total sample

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size of at least 110 women in both groups (55 in each group) using 80% power would
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be necessary to detect 2 cm difference in the VAS pain score with the use of LP cream

[Odds Ratio=0.6]. We expected a 10% dropout rate; and therefore recruited 120
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women to the study'

All data were analyzed using SPSS software Chicago, IL, USA, version 21.
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Comparison between categorical variables in both groups was done by Chi-square test
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or Fisher’s exact test if appropriate and continuous variables were compared using
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Student T-test. For statistical analysis, we tested the different pain scores for normality

by Shapiro-Wilkes test and they were not normally distributed, so they are presented

as median scores and compared using the Mann-Whitney test. The ease of insertion

scores were normally distributed, so they are presented as mean ± SD and compared

with the Student T-test. A multivariate stepwise linear regression model was

conducted, after controlling for the interventional arm, to assess to assess if any

baseline characteristics were associated with increased pain. We considered P value <

0.05 as a significant value.

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3- Results:

We recruited 131 women to participate in the study. Eight women have been

excluded: five women had uterine abnormalities and three women had received

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analgesics prior to insertion. Moreover, three women declined participation in the

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study after signing the approval consent form. We randomly assigned the remaining

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120 women into both groups (Figure 1, the study flowchart). The day of the menstrual

cycle ranged from the second to the fifth at insertion.

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Table 1 show that both groups were comparable in the baseline characteristics.
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Table 2 shows the median pain scores for both groups. Women in the LP group were

more likely to report clinically significant lower pain scores during IUD insertion, during
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tenaculum placement and uterine sound insertion (p=0.0001). The difference in pain

scores at 5 min after IUD insertion did not show a clinical significance. A lower ease of
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insertion score was also determined among LP group (p=0.001).

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Six women asked for additional analgesics in the placebo group versus one in the
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LP group (p=0.114). The groups were similar with regard to tenaculum site bleeding.

No cases of uterine perforation or vasovagal reactions in both groups. Also, no

reported side effects from LP use (Table 2).

Regression analysis of baseline characteristics as predictors of pain revealed that

reproductive age 30 years or more, parity, women's education, Cesarean deliveries,

menstrual pain, and prior perineal laceration requiring suture repair were not

predictors for pain experienced during IUD insertion. Moreover, pain scores were not

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affected by the gynecologist who insert the IUD (p=0.19), prior IUD insertion (p=0.3),

and prior office gynecologic procedures (p=0.26).

4- Discussion:

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Pain during IUD insertion is multifactorial; application of the tenaculum on the

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cervical lip can induce severe pain. In addition, insertion of sound and IUD inside the

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uterine cavity can add to pain perception [16]. Transmission of Pain from the uterus

occurs through two different visceral pain pathways; Parasympathetic (S2-S4) provides

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sensory innervation to the cervix and lower portion of the uterus and sympathetic
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(T10-L1) provides sensory innervation to the fundus [17]. In the current RCT, we found

that LP cream applied on the cervix prior to copper T380A IUD insertion significantly
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decreased the IUD insertion pain.

Local anesthetics used prior to IUD insertion include a number of formulations

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(e.g. gel, injections and spray) and different techniques for administration (intracervical
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and paracervical) [8, 18-22]. They have several advantages; however, no studies have
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provided strong evidence that various lidocaine formulations provide significant pain

relief for women undergoing IUD insertion [5].

LP cream seems to be successful in providing pain relief. When applied to a

mucous membrane, it is rapidly absorbed within 5-7 minutes compared with 1 hour if

applied to skin [23]. The optimal time for application on the genital mucosa is between

5 and 10 minutes as reported by Van der Burghat et al [24]. In our study, we allowed 7

minutes to elapse between its application and IUD insertion, and based on the results,

this time period was sufficient for the drug to take effect. We found most of the

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applied cream stayed on the cervix at the end of 7 minutes and a cotton swab was

used to wipe-out the residual cream before cervical manipulations.

Our results showed significant lower pain scores in all steps of IUD insertion in LP

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group as compared with placebo group (p=0.0001). Inserting the IUD tube was the

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most painful step and those who received LP had less pain as compared with placebo

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group (3[2-3] vs. 6.5[4-8], p=0.0001). In contrast to Tavakolian et al [25], insertion of

the sound was the most painful step in the procedure (5.2±2.3 in the placebo group vs.

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3.1±2.5 in LP group, p<0.001). MA
In the current study, the median pain score during IUD insertion was 6.5 (range 4-

8) for women in the placebo group. This is not coincides with the results obtained by
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Fouda et al, 2016 that was carried out in Egypt [6]. The baseline characteristics of the

study participants are quite different. In Fouda et al study, the participants were
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recruited from Cairo; the capital city of Egypt. In our study, most of women live in rural
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areas. The living conditions can affect the way of pain perception for some women.
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Safety and efficacy of LP have been revealed consistently in many clinical trials in

office gynecological procedures. Liberty et al., 2007 and Arnau et al., 2014 [13, 26]

proved that LP cream significantly reduces the pain associated with cervical

instrumentation by tenaculum and cannula application during HSG (3.3±2.9 vs.

4.9±2.7, p=0.02 and 1.06 vs. 3.34, p=0.000, respectively). These studies are consistent

with our findings. On the contrary, Arnau et al., 2013 [27] in their study of LP cream

before hysteroscopy reported no significant reduction in the procedure associated

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pain (p=0.07). The small sample size and the non-blinded nature of the study may

explain the difference with our results.

LP cream has a high safety profile with rare adverse effects. Reported side effects

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include local skin reactions, burning sensation, erythema and pruritis [28]. In our study,

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no reported local or systemic side effects in women received LP cream within 24 hours.

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This coincides with the study of Liberty et al [13] in which 41 women received LP cream

before HSG with no adverse effects reported.

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The strengths of our study include that it was a double blind, randomized, clinical
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trial with neither women nor the clinicians being aware of the group assignment. Also,

we included different educational levels of women, as this could affect the perception
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of pain, so our results could be generalizable to different women in our community.

Finally, we were able to recruit our calculated sample size for achieving sufficient
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power to detect a clinically significant difference in our primary outcome.

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The study had its limitations including that the study focused on one type of IUD
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as the levonorgestrel IUD is not widely used in Egypt due to its high cost, and

consequently the data are applied only for the copper IUD. A second limitation was the

subjectivity in reporting pain through VAS score, as there are no objective parameters

to evaluate pain. Furthermore, none of the included women were nulliparous as IUD

insertion is not requested by this group in Egypt. Also, adding 7 minutes to the

duration of complete IUD insertion could be a source of potential discomfort of a

lengthy procedure with speculum in situ for some women. The participants in this

study did not offer complaints about leaving the speculum in place for 7 additional

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minutes. We used a small plastic speculum in the procedure to avoid any discomfort or

pain induced by the metal one that can affect the pain scores. Also, all participants

viewed the plastic speculum during the pre-insertion counseling. Finally, the possibility

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of inter-assessor variability between the four clinicians involved in IUD insertion.

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However, the comparable experience in IUD insertion and their equal distribution in

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both study groups minimized this risk.

In conclusion, topical application of LP cream on the cervix prior to copper T380A

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IUD insertion seems to significantly alleviate the induced pain with subsequent easy
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insertions. It is easily applied and relatively inexpensive with no side effects. Further

studies are needed to explore its effectiveness in women at high risk for experiencing
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severe pain during insertion as nulliparous women or those who only delivered by

elective CS. Moreover, further studies are needed to directly compare its effectiveness
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with various local anesthetics in alleviating IUD insertion pain.

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5- Conflict of interest:
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None.

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[23] Ljunghall K, Lillieborg S. Local anaesthesia with lidocaine/prilocaine cream (EMLA)

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Figure captions:

Figure1. Flowchart of the study participants randomized to cervical lidocaine-

pridocaine cream before copper IUD insertion versus placebo.

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Table 1: The baseline characteristics of the women according to the medication used prior

to IUD insertion

Characteristics LP Group (n=60) Placebo group (n=60) P- value

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Age (years) 31.1 ± 6.2 31.4 ± 6.7 0.79

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Residence

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Urban 23 (38.3) 27 (45.0) 0.58

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Rural 37 (61.7) 33 (55.0)

Education

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Some high school 10 (16.7) 13 (21.7)
High school 18 (30.0) 27 (45.0) 0.15
College 20 (33.3) 14 (23.3)
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Postgraduate 12 (20.0) 6 (10.0)
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Parity 3.2 ± 1.0 3.3 ± 1.7 0.60

Previous miscarriages 19 (31.7) 18 (30.0) 0.58
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Previous VD 32 (53.3) 27 (45.0) 0.47

Previous CD 38 (63.3) 39 (65.0) 0.50
Previous only CD 28 (46.7) 33 (55.0) 0.32
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Number of CD 1.1 ± 1.1 (0-4) 1.4 ± 1.4 (0-5) 0.19

AC

Previous insertion of IUD 34 (56.7) 27 (45.0) 0.24

Duration of insertion 3.1 ± 0.9 3.34 ± 1.0 0.27
Menstrual pain 11 (18.3) 9 (15.0) 0.81
Office gynecological procedures 9 (15.0) 8 (13.3) 0.50
#
Perineal trauma 13 (21.7) 8 (13.3) 0.34
LP; lidocaine-prilocaine, VD; vaginal delivery, CD; Cesarean delivery, IUD; intrauterine device.
All data are presented as n (%) or mean ± standard deviation.
#
Perineal trauma means perineal laceration during birth requiring suturing repair

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 ACCEPTED MANUSCRIPT

Table 2: The principal outcomes during IUD insertion according to the medication used prior

to the procedure

Study Outcomes LP Group Placebo group P- value

T
(n=60) (n=60)

P
VAS tenaculum placement 2 [2-3] 4 [3-6] 0.0001

RI
VAS sound insertion 3 [2-3] 6 [5-9] 0.0001
VAS IUD insertion 3 [2-3] 6.5 [4-8] 0.0001

SC
VAS 5 minutes post-insertion 2 [1-2] 3.5 [2-6] 0.0001
Ease of insertion score 2.5 ± 0.98 4.5 ± 1.7 0.001

NU
Need for additional analgesics 1 (1.7) 6 (10.0) 0.11
Tenaculum site bleeding MA 1 (1.7) 2 (3.4) 0.56
Uterine perforation 0 0 ------
Side effects of study medication 0 0 ------
LP; lidocaine-prilocaine, VAS; visual analog scale, IUD; intrauterine device.
ED

All data are presented as n (%), median [inter-quartile range] or mean ± standard deviation
PT
CE
AC

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