Lidocaine Prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study

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1 Human Reproduction Vol.22, No.5 pp , 2007 Advance Access publication January 18, 2007 doi: /humrep/del517 Lidocaine Prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study G.Liberty 1,3, M.Gal 1, T.Halevy-Shalem 1, R.Michaelson-Cohen 1, N.Galoyan 1, J.Hyman 1, T.Eldar-Geva 1, E.Vatashsky 2 and E.Margalioth 1 1 Department of Obstetrics and Gynecology and 2 Department of Anesthesia, Shaare Zedek Medical Center, Jerusalem, Faculty of Health Science, Ben-Gurion University of the Negev, Beer Sheba, Israel 3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem. liberg@013.net.il BACKGROUND: The aim of our study is to evaluate the efficacy of applying lidocaine 25 mg prilocaine-25 mg/g cream (EMLA 5%) on the uterine cervix for pain relief when performing hysterosalpingography (HSG). METHODS: Eighty-two patients undergoing HSG as part of infertility evaluation were randomized into groups receiving EMLA (42) or placebo cream (40) in a double-blinded prospective study from which four women were later excluded. The cream was applied to the uterine cervix by means of a cervical cup 30 min before the HSG. Pain perception related to the HSG procedure was scored by visual analogue scale (VAS) at five predefined steps: after speculum application, after cervical instrumentation of the tenaculum and cannula, at the end of uterine filling, at completion of tubal spillage, and immediately following instrument removal. In addition, the patients were asked to retrospectively rate the pain during the entire procedure in a telephone interview the following day. RESULTS: Cervical instrumentation was found to be the most painful step of HSG (P <0.001). When comparing the VAS pain scores, cervical instrumentation in the EMLA-treated patients was associated with significantly less pain than the control group: versus , respectively (P ). CONCLUSION: Topical application of EMLA 5% cream on the uterine cervix before performing HSG significantly reduced the pain during this procedure. Key words: hysterosalpingography/local anaesthetic/pain relief/uterine cervix/visual analogue scale Introduction Hysterosalpingography (HSG) is an important tool in the evaluation of infertility. Due to its reliability and costeffectiveness, it is the most commonly used method for evaluation of anatomy and patency of the uterus and fallopian tubes (Mol et al., 1999; ESHRE Capri Workshop Group, 2000; Taylor, 2003). A major disadvantage of this procedure is the pain associated with it. Eighty five percent of patients who undergo this procedure report pain, with half complaining of moderate to severe pain (Costello et al., 2002). A number of methods have been used to reduce pain during HSG, such as use of a balloon catheter instead of a metal cannula or substituting aqueous-based instead of oil-based contrast media (Moore, 1982; Varpula, 1989). Oral analgesics have also been explored as a means for pain reduction. Fenoprofen, naproxen (both non-steroidal anti-inflammatory drugs) and tramadol were found to alleviate pain during the HSG procedure, however paracetamol was found to be ineffective (Owens et al., 1985; Peters et al., 1996; Elson and Ridley, 2000). Opiod analgesia with intravenous remifentanil was also found to be superior to placebo for HSG (Cengiz et al., 2006); however, the need for special care following IV narcotics and resultant costs make this intervention unfeasible. Lidocaine and lignocaine, both local anaesthetics, inserted into the uterus before the procedure, were found to be ineffective in reducing HSG pain (Costello et al., 2002; Frishman et al., 2004). However, 20% benzocaine gel applied on the uterine cervix significantly decreased discomfort during the examination (Lorino et al., 1990). EMLA 5% cream is composed of two local anaesthetics, lidocaine 25 mg and prilocaine 25 mg/g. Its application on the cervix is painless. It had been used locally on the uterine cervix before laser ablation and hysteroscopy and was found to reduce the patient s pain (Zullo et al., 1999; Zilbert, 2002). In a previous prospective cohort study, we investigated the application of EMLA on the uterine cervix before HSG for # The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 1335

2 G.Liberty et al. pain relief during the procedure (Liberty et al., 2005). We found that cervical instrumentation was the most painful step during the procedure and that use of EMLA cream decreased the pain in this step. In the current study, we aimed to investigate whether the usage of EMLA 5% on the uterine cervix reduces the pain associated with this procedure in a prospective randomized, double-blind, placebo controlled study. Materials and methods Power and sample size calculations were carried out on the basis of the results of our previous study (Liberty et al., 2005). A difference of at least 1.5 VAS score (see below) at cervical instrumentation (30% of the mean VAS score in the untreated group) with highest standard deviation of 2.5 would be regarded as clinically significant. With assumption of a error as 0.05 with power of 0.8, a sample size of 35 patients in each treatment group was required. The study was approved by the research ethics committee of the Shaare Zedek Medical Center, Jerusalem. Between February 2005 and December 2005, 91 consecutive patients underwent HSG as part of an infertility evaluation and were included in this study. Written consent was gained following explanation by a trained physician. Exclusion criteria were known hypersensitivity to local anaesthetics and use of oral analgesics before the procedure. Eighty-two women were enrolled in the study after exclusion of nine patients. HSGs were performed by four different trained physicians. Operators were randomly assigned to perform the procedures and were blinded to treatment modality. Patients were randomized to EMLA or control groups using computer generated random numbers. The allocation was concealed until the statistical evaluation of the results. Forty-two were randomized to the EMLA-treated group, and 40 to the placebo-control group. During the procedure, one patient from the EMLA-treated group and three from the control group dropped out due to lack of patient co-operation (NS). Forty-one patients in the EMLA-treated group and 37 in the untreated, control group were analysed. No differences were found between the study group and the excluded group in the background parameters. Both the HSG operator and the patient were blinded to the randomization. In both groups, cervical cups (PRODIMED, NEUILLY EN THELLE, France) were filled with 3 ml of creams, identical in colour, smell and texture according to randomization. An independent medical staff not performing the HSG prepared and dispensed either EMLA or placebo to the doctor that were blinded to the randomization. The cap was placed on the uterine cervix using a vaginal speculum and a ring forceps 30 min before the procedure by a doctor not performing the HSG. In the treated group, EMLA 5% cream (ASTRA PHARMACEUT PRODUCTION, SODERTALJE, Sweden) was administered, whereas a placebo cream was used in the control group. All patients were asked to score the pain during the procedure using the visual analogue scale (VAS) as described (review Katz and Melzack, 1999). The VAS consisted of a 10-cm line scaled from 0 to 10 (0 ¼ no pain and 10 ¼ severe pain). Patients were asked to specify the number that represented their level of perceived pain intensity. A detailed explanation about the VAS and its application was given personally to each woman before the procedure. The HSG procedure was performed with a woman placed in a modified lithotomy position on the fluoroscopic table. A sterile bivalve speculum was introduced into the vagina to expose the uterine cervix. The cervical cup was removed at this point of time. The vagina and cervix were washed with antiseptic 1% chlorhexidine solution and a single-toothed tenaculum was placed on the anterior lip of the cervix. The placement of the tenaculum was coordinated with the patient giving a forceful cough. A metal cannula was gently inserted into the external cervical os and a water soluble radio opaque dye was injected (TELEBRIX 350, GUBERT laboratories, France). The contrast medium was injected slowly to prevent pain, and spot fluoroscopic images were obtained. At the end of the procedure, the instruments were removed and the patient remained for half an hour in the clinic for observation, before discharge. In both study groups, the pain during the procedure was scored at five consecutive steps: (i) After speculum application, before instrumentation. (ii) After application of the tenaculum and the cannula on the uterine cervix (cervical instrumentation), just before contrast media injection to the uterus. (iii) At the end of uterine filling with contrast media. (iv) At the end of tubal spillage with contrast media. (v) At the end of the procedure after the tenaculum and cannula were removed. At each stage of the procedure, the patient reported the VAS score, which was recorded in real time by a medical observer blinded to the randomization. In addition, on the day after the procedure, all patients were interviewed by telephone and asked to retrospectively score the pain of the entire HSG procedure. During the procedure, the operator reported the absence/presence of the following: (i) Difficulty in instrument application. (ii) Use of tension to fill the uterus with contrast medium. (iii) Application of tension to the cervix. (iv) Difficulty in instrument removal. Pathologic results that may be associated with pain during the procedure, such as fallopian tube occlusion or evidence of pelvic adhesion, were noted in the patient s file. Statistics The pain scores of the EMLA-treated group and the placebo-control group as reported by the patients were compared. In order to compare quantitative variables from the EMLA-treated and the control groups, Student s t-test, as well as non-parametric Mann Whitney U test were applied. Chi-square test and Fisher s exact test were used to assess differences between the study groups for qualitative parameters. The Pearson correlation coefficient was calculated to estimate the association between pairs of quantitative variables, and finally a paired t-test was used to check whether the differences within each study group were significant for quantitative variables. Results are presented as means + SD, unless otherwise indicated. All tests applied were two-tailed, and a P-value of 5% or less was considered statistically significant. Results Eighty-two women were enrolled in the study; 42 were randomized to the EMLA-treated group and 40 to the control group. Four women were excluded from the analysis due to lack of co-operation: they failed to accomplish the VAS, the initial agreement (one in the EMLA group and three in the control group). Background, demographic and clinical details were found to be similar in both groups (Table I). In order to evaluate the pelvic and gynaecologic pain associated histories, 1336

3 EMLA for pain relief in HSG Table I. Demographic data and pelvic pain associated history a Controls (n ¼ 37) EMLA-treated (n ¼ 41) Age (years) Infertility duration (years) Primary infertility (%) 16/36 (44) 17/41 (42) Nuliparity (%) 26/37 (70) 25/41 (61) Dysmenorrhea (%) 20/36 (55) 20/41 (49) Dyspareunia (%) 6/36 (17) 9/40 (22) Past PID (%) 1/37 (3) 2/40 (5) Past gynecological operative/ 11/37 (30) 12/41 (29) D&C procedure (%) Past vaginal delivery (%) 11/37 (30) 16/41 (39) Past Cesarean Section (%) 4/37 (11) 4/41 (10) Past abortion (%) 13/37 (35) 12/41 (30) a Discrepancies between the denominator and the original patient number in each group are due to missing data. we compared the relevant parameters between the two study groups. No significant differences were found (Table I). In the operator s self-assessment of technical difficulties encountered during the procedure, there were no reported significant differences between the EMLA-treated and the control groups (Table II). To enable the patients to describe the pain during the entire procedure, the HSG was divided into five discrete steps as detailed earlier. The mean pain at base line (step 1) was similar in the placebo and the EMLA-treated groups ( versus , respectively. P ¼ 0.6). Cervical instrumentation (step 2) was significantly more painful than the other steps of the procedure (steps 3 5) in the control group (P, 0.001). At this specific step, the EMLA-treated patients reported significantly less pain than the placebo patients ( , 95% confidence interval (CI) versus , 95% CI , respectively, P ¼ 0.02). The use of EMLA reduced the pain recorded on the VAS at cervical instrumentation by (95% CI ), compared with placebo. No differences between the study and the control groups were found in the less painful steps (3 5) such as uterine filling, tubal spillage and removal of instruments ( versus , versus and versus , respectively) (Figure 1). In an attempt to exclude any bias in comparing pain assessment between the groups, we have reanalysed the results without those cases in which the operator had difficulty with the cervical instrumentation (three women in the EMLA group and seven women in the control group) and those cases where the VAS score at baseline (step 1) was extraordinarily high (eight or more) (four women in the EMLA group and three women in the control group). We found an even higher statistically significant difference in the VAS pain score in this step ( , 95% CI versus , 95% CI ) in the EMLA-treated and the control groups, respectively (P ¼ 0.004), whereas there were no differences in other steps. On the following day (step 6), the EMLA-treated group retrospectively reported less pain ( , 95% CI versus % CI pain score) although this was not quite statistically significant (P ¼ 0.06) (Figure 1). However, there was a strong correlation between the VAS pain scores at the most painful procedure step (step 2) and the pain scored on the following day (step 6) in both the EMLA-treated and the control groups (r ¼ 0.669, P, and r ¼ 0.700, P, 0.001, respectively). The HSG procedures were performed by four different operators. Analysis of the pain scores given to each operator revealed that one operator received significantly lower VAS pain scoring during the step of cervical instrumentation and on retrospective reporting the following day. Re-analysis of the pain scores, with exclusion of the scores of this specific operator (four from the EMLA and three from the control group), emphasized the significant differences between the control and EMLA groups for step 2 cervical instrumentation ( , 95% CI versus , 95% CI , P ¼ 0.005) and step 6 retrospective reporting ( , 95% CI versus , 95% CI , P ¼ 0.01), whereas there were no differences in other steps. In both groups, pathological results were noted in 26% of the women. In the placebo-treated group, the pain scores during the cervical instrumentation were higher in those with the pathology than in those with the normal results ( versus , a mean difference of , 95% CI , P ¼ 0.04). However, in the EMLA-treated group, no difference was found between those with and without pathology at this step ( versus , a mean difference of , 95% CI , P ¼ 0.4). No differences at the other steps were found in both groups. No signs of local or systemic reactions were seen in any of the EMLA-treated patients. Discussion Cervical grasping and cannula instrumentation is the initial step in performing HSG. We investigated the analgesic effect of EMLA 5% cream on the uterine cervix at five discrete consecutive steps in the HSG procedure. We found cervical Table II. Operator self-assessment of technical difficulties a Controls (n ¼ 37) EMLA treated (n ¼ 41) P-value b Difficulty in instrument application (%) 7/34 (21) 3/38 (8) 0.1 Uterine filling under pressure (%) 5/35 (14) 7/40 (17) 0.7 Tension applied to cervix (%) 23/35 (66) 24/41 (58) 0.5 Difficulty in removal of instruments (%) 2/34 (6) 0/41 (0) 0.1 a Discrepancies between the denominator and the original patient number in each group are due to missing data. b x 2 -test. 1337

4 G.Liberty et al. Figure 1. Visual analogue pain scores (VAS) (mean + SEM) at six different points during the HSG procedure, in the EMLA-treated (thick line) and control (thin line) groups. instrumentation to be the most painful. Patients who were treated with local anaesthetic had significantly less pain at this step. Furthermore, when we eliminated the cases with difficult cervical instrumentation or the cases where HSG was performed by the doctor with the exceptional VAS, the difference between the groups became even more pronounced with significantly less pain both at the time and retrospectively reported the following day. According to Costello (Costello et al., 2002), a reduction of 15% was considered to be of clinical significance. Our study demonstrated a reduction of over 30%, with scores reaching baseline level (step 1). The clinical importance is reinforced by the strong correlation with the retrospective scores, indicating that this difference had a meaningful impact on our patient population. EMLA 5% was applied on the uterine cervix to decrease pain, with the assumption that this initial step is the most painful. Different anatomic sites in the reproductive tract are affected during the HSG procedure, which includes cervical irritation (instrumentation), uterine distension (injection of contrast media) and peritoneal irritation (tubal spillage). The sensory fibers from the body of the uterus pass through the 11th and 12th thoracic nerve roots to the central nervous system, whereas the sensory nerves from the cervix pass through the pelvic nerves to the second, third and fourth sacral nerves (Williams obstetrics 21st edition, 2001). Thus, local anaesthesia, which affects the uterine cervix, does not affect the pain generated on the uterine body. In a previous study, it was found that 93% of patients experienced pain after the first 5 min of the HSG procedure in comparison to 67% after the first 10 minutes and 40% after the first 15 min (Owens et al., 1985). In concordance with this report, we 1338 found cervical instrumentation to be the most painful step. These results are compatible with our previous prospective cohort study (Liberty et al., 2005). In contrast to pain relief with anaesthetic applied to the cervix, no pain reduction following intrauterine application of lignocaine or lidocaine, when used immediately before HSG performance, was achieved (Costello et al., 2002; Frishman et al., 2004). These findings may be explained by our findings that the cervical instrumentation is the most painful step and not the uterine filling and tubal spillage. In addition, the use of local anaesthetic by intrauterine application may achieve its effect only on the endometrium and the superficial myometrium, while the pain may be activated by the distension of the entire uterine myometrium. The onset, depth and duration of dermal analgesia provided by EMLA depend primarily on the duration of application. When using EMLA 5% cream on the vulval mucosa before condylomata acuminate cauterization, the most effective degree of anaesthesia was achieved after 5 15 min. seventy-five minutes after application, the EMLA 5% still had an anaesthetic advantage over the placebo (Ljunghall et al., 1989; Rylander et al., 1990). The cervical cap we used allowed additional continuous application of the local anaesthetic to the cervix for 30 min prior to the procedure. We are aware of only one previous randomized controlled study comparing local anaesthetic and placebo during HSG (Lorino and Lilliborg, 1990). Twenty women who were treated with topical application of 20% benzocaine gel on the uterine cervix were compared with the placebo group. The authors have found a significant reduction in pain during HSG with topical cervical anaesthesia, in accordance with our study. Only 10% of the treated group had severe pain in

5 EMLA for pain relief in HSG comparison to 45% of the placebo group. In this small study, the discrete site and timing of pain were not specified. The effect of local anaesthetic has been examined in hysteroscopy, another procedure involving instrumentation of the cervix. Comparison between lignocaine spray and placebo demonstrated a significant reduction in pain during attachment of the tenaculum in the group that underwent treatment with lignocaine spray (Davies et al., 1997). By comparing the efficacy of lignocaine prilocaine (EMLA) cream and lignocaine jelly during hysteroscopy, a significant reduction in pain was achieved by the lignocaine prilocaine cream (Zullo et al., 1999). These studies are consistent with our findings that local anaesthesia with lidocaine prilocaine cream to the cervix reduces pain during cervical manipulation. We would have expected to find more pain reported by women with pathological HSG findings- i.e. tubal occlusion and pelvic adhesions, during the steps of uterine filling and tubal spillage (steps 3 and 4). To our surprise, there was no significant difference at these steps of the procedure between the pain scores reported with pathological versus normal HSG results. However, we found that in the placebo-control group (but not in the EMLA group, although this may reflect the small number of patients in each group), women with pelvic pathology reported more pain during cervical instrumentation (step 2) ( versus , P ¼ 0.04). This may be due to the traction of the pelvic adhesions during the instrument application on the cervix. We found a strong correlation between the VAS pain scores at the most painful procedure step (step 2) and the pain scored retrospectively on the following day (step 6), in both the EMLA-treated and the control groups. This may demonstrate how pain relief during the cervical instrumentation not only reduces pain during the procedure, but also can impact on long-term pain perception. In conclusion, topical application of EMLA 5% cream on the uterine cervix before HSG significantly reduced the pain associated with this procedure with no side effects. The longterm pain perception was also reduced. It is easily applied and relatively inexpensive. We recommend the routine use of EMLA 5% cream before every HSG procedure. Further research is needed before the recommendation of this form of analgesia for other gynaecological procedures involving the uterine cervix. Acknowledgements The authors are grateful to Mrs Shoshana Kremer, Mrs Sarah Ohev- Zion and Mrs Rachel Kimelmann, the nurses of the Fertility Clinic in Shaare-Zedek Medical Center for their invaluable assistance and Tali Bdolah-Abram for statistical analysis of the results. 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