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Topical Anesthetic (Lidocaine-Prilocaine) Cream Application Before Speculum Examination in Postmenopausal Women
Original Article
Topical Anesthetic (Lidocaine-Prilocaine) Cream Application Before Speculum Examination in Postmenopausal Women Aktepe Esra Keskin, MD*, Yuksel Onaran, MD, Iltemur Candan Duvan, MD, Serap Simavli, MD, and Hasan Kafali, MD From the Department of Obstetrics and Gynecology, Fatih University Medical School, Ankara, Turkey (all authors).
ABSTRACT Study Objective: To evaluate the effectiveness of lidocaine–prilocaine (EMLA 5%) cream application to genital mucosa for reducing pain or discomfort associated with speculum examination in postmenopausal women. Design: A randomized controlled study (Canadian Task Force classification I). Setting: A university hospital. Patients: One-hundred thirty-four postmenopausal women. Interventions: The subjects were randomized to an EMLA cream group, a lubricant gel group, or a control group. General data was collected, including age, body weight, gravidity, parity, smoking habits, history of diabetes mellitus, previous gynecologic operations, dyspareunia, sexual activity, and duration of menopause. All patients were asked to score pain at 3 time points (insertion, dilation, and extraction of speculum) during the procedure using a visual analog scale. Pain intensity during speculum examination was compared between the groups. Measurements and Main Results: There was no statistically significant difference between the EMLA cream, the lubricant gel, and the control groups in terms of age, weight, gravidity, parity, dyspareunia, duration of menopause, sexual activity, smoking habit, diabetes mellitus, previous vaginal and other gynecological procedures, vaginal length, and serum folliclestimulating hormone and estradiol levels (p . .05). The pain scores obtained during all phases of speculum application were significantly lower in the EMLA group than in both the lubricant gel and the control groups (p , .001). Comparing the gel and the control groups, a lower pain score was observed in the former, except for the second phase of the examination (p , .001). Conclusion: Topical application of EMLA 5% cream on genital mucosa of postmenopausal women before vaginal examination significantly reduces pain associated with speculum application. Journal of Minimally Invasive Gynecology (2012) 19, 350–355 Ó 2012 AAGL. All rights reserved. Keywords:
DISCUSS
Topical anesthetic; Lidocaine; Prilocaine; Speculum examination; Postmenopause
You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-19-3-11-00446
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
Pelvic examination, an important part of preventive health care for adult women, is performed to help detect certain cancers in their early stages, infections, or other reproductive system problems. Despite its importance, many women are reluctant and anxious about the procedure beThe authors declare that they have no conflict of interest. Corresponding author: Aktepe Esra Keskin, MD, Birlik mah. 450. cad. 499. sok. No: 3/5 C ¸ ankaya, 06610 Ankara, Turkey. E-mail: [email protected] Submitted October 13, 2011. Accepted for publication January 5, 2012. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2012 AAGL. All rights reserved. doi:10.1016/j.jmig.2012.01.005
cause of potential embarrassment, apprehension, and fear, as well as discomfort and pain [1]. The female genital mucous membrane is highly sensitive to pain, which is increased in the presence of atrophy and inflammation [2]. Because estrogen levels decrease at menopause, women often experience a variety of adverse vaginal symptoms, including dryness, loss of tone, irritation, hyperalgesia, and pain, which may be exacerbated during intercourse and vaginal examination [2–4]. These symptoms are generally attributed to declining estrogen levels, which result in an increase in a subset of vaginal sensory nerve endings and in profound atrophic and inflammatory changes in vaginal
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Anesthetic Cream Application Before Speculum Examination in Postmenopausal Women
tissue [2]. Therefore speculum application is even more anxiety-provoking and difficult during the postmenopausal period [5]. Topical anesthetics have been extensively studied in adults and children for a range of needle procedures, including vaccination, intravenous cannulation, venipuncture, and dermatologic procedures, such as split-skin grafting and removal of genital warts [6]. A number of topical anesthetics have been investigated for different indications involving the genital mucosa, including Eutectic Mixture of Local Anaesthetics (EMLA) 5% cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), benzocaine 20% gel, cocaine spray, 2% mepivacaine, 2% lidocaine gel, and 1% tetracaine [6]. EMLA cream is an oil-in-water emulsion of 2.5% lidocaine and 2.5% prilocaine that optimizes the absorption through intact skin. EMLA penetrates a mucosal surface faster than keratinized epithelium on female genitourinary mucosa [7]. EMLA cream provided the most effective degree of anesthesia after 5 to 10 minutes of application time on the genital mucosa [8,9]. The quality of analgesia decreases with application times longer than 10 to 15 minutes [8,9]. The female genital mucous membrane is highly sensitive to pain. Eutectic lidocaine/prilocaine cream is a formulation of local anesthetics that has proven to be effective and well tolerated in the relief of pain associated with various minor gynecologic interventions [6]. Procedures for which local anesthetics and analgesics are appropriate include removal of genital warts by laser surgery [8,10], thermocautery, or cryotherapy [9]; colposcopic assessment; vaginal, vulvar, cervical, and endocervical biopsies [11]; laser treatment of preinvasive cervical lesions [12]; hysteroscopy [13]; and hysterosalpingography [14]. Because these procedures are relatively superficial, topical anesthesia is a logical option with respect to these procedures and avoids the risks associated with other methods of anesthesia. However, to date, the application of a topical anesthetic during speculum examination has not been studied. EMLA cream has been shown to be safe and efficacious in geriatric patients, but its use is controversial in neonates [15–17]. The aim of this randomized controlled study was to estimate the effectiveness of EMLA cream application to the genital mucosa for pain or discomfort associated with speculum examination in postmenopausal women. Materials and Methods A total of 147 postmenopausal women, aged between 55 and 65 years and not taking hormone therapy for at least 3 months or ingesting prescription or nonprescription herbal medications, were recruited into the study. All candidates gave written informed consent before study entry. Postmenopausal status was determined by menstrual cycle history, as well as follicle-stimulating hormone (FSH)
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(.25 mIU/mL) and estradiol (,25 pg/mL) levels at time of entry into the study. Women with known hypersensitivity to local anesthetics or to oral analgesics were excluded. A complete physical examination and medical history were obtained from all study participants. General data, such as age, body weight, gravidity, parity, smoking habit, history of diabetes mellitus, previous gynecologic operation, dyspareunia, sexual activity (1 or more times per month was accepted as sexually active), and duration of menopause, was collected. Subjects were assigned randomly to receive lidocaine 25 mg plus prilocaine 25 mg/g cream (EMLA, AstraZeneca, Wilmingston, DE); lubricant gel (Ty & Ja; Dr. M€uller Pharma, Hradec Kralove, Czech Republic), a fluid and semisolid gel with high content of water and containing hydroxyethylcellulose; or to a control group. The randomization sequence that was used in this trial was generated by a computerized random-number generator. The allocation was concealed until the results were statistically evaluated. A total of 48 women were randomized to the EMLA cream group, 46 to the lubricant gel group, and 53 to the control group. During the procedure, 13 subjects were excluded from the study for the following reasons: 2 (1 from lubricant gel group and 1 from control) had passed urine after the application of gel; 4 (1 from the EMLA group, 3 from the control group) did not tolerate the procedure just at the initial point, before the agents were applied, or the speculum was inserted (the cases did not give permission to apply the agents or insert the speculum when they were still in the lithotomy position, and in those cases the pain intensity could not be assessed); 4 (one from the EMLA group, 3 from the control group) were removed because of lack of cooperation; and 3 (1 from the EMLA group, 2 from the control group) had additional procedures carried out other than a vaginal examination (1 had a cervical polyp removed, and 2 had endometrial sampling performed). All patients enrolled in the study were asked to score the pain at 3 time points during the procedure using a Visual Analog Scale (VAS). The VAS consisted of a 10-cm–long straight line, scaled from 0 to 10 (0 5 no pain and 10 5 severe pain) without numerical values on the scale, except for ‘‘0’’ at the initial and ‘‘10’’ in the end. Patients were asked to specify the point that represents their level of perceived pain intensity. After the subjects had marked for each pain on the scale, the distance of the points from ‘‘0’’ point was measured with a ruler and recorded. A detailed explanation of the VAS and its application was delivered personally to each woman before the procedure. All patients were examined in the lithotomy position at 30- to 45-degree angles to the examination table. All women were draped with a full-sized sheet in a standardized manner that maximized coverage of the woman and allowed visualization of the perineum. A sterile, bivalve, medium-sized Grave’s disposable plastic speculum of a standard size with dimensions 90 ! 23 mm and an external light source were used for all examinations.
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In the EMLA group, EMLA cream 5 g was applied to the perineum and vaginal orifice and introduced as deeply as possible with the physician’s finger. The commercial type of EMLA cream is available and marketed in 5-g amounts in small tubes that are suitable for single use. For this reason, we decided to use this amount for both agents to be able to fix the standardization. The speculum examination followed 5 minutes later. In the lubricant gel group, the same procedure was performed with same amount of gel. The agents were applied by 5 physicians, and the mean length of their index fingers was 7.1 6 0.7 cm. In the control group nothing was applied to the perineum or to the vagina. For all patients, speculum insertion was performed as follows. The speculum was warmed, and patients were informed about what was going to happen. The labia were spread from below to introduce the speculum, which was inserted at a 45-degree angle pointing downward then rotated horizontally as the insertion continued. A VAS score (insertion) was obtained at this point. Next, the bill of the speculum was opened up until the cervix could be seen, and the speculum was secured by turning the thumbnut. A second VAS score (dilation) was recorded. During speculum examination, the specimens (cervical smear with cervical brush and cervicovaginal culture with a swab) were obtained for pathologic and microbiologic assessment, and vaginal length was measured with a ruler. The speculum was withdrawn slightly, which allowed the bill to close together, and at this stage (extraction) the final VAS score was obtained. At each stage of the procedures, VAS scores were recorded in real time by the same medical observer (S.S.) blinded to the randomization. The observer joined the study just before the speculum was inserted. She did not have any knowledge about whether any agent was applied to the cases. Before the study was carried out, a total sample size of 138 subjects (46 cases per groups) was calculated to conform to the following statistical requirement: effect size (f) 40% difference between groups with decreasing pain intensity according to VAS, type I error (a) 5 .05, type II error (b) 5 .10, and power 5 90%. The effect size was determined according to the results of the pilot trial performed on the 15 cases (5 cases for each group) before the study was constructed. Because the pain intensity is perceived the most during the dilation stage, the pain intensities of this stage were considered the reference intensity to find the difference between the groups with an agent (EMLA or lubricant gel) and the control group. A 40% difference between the VAS score means of the groups was considered clinically significant. However, at the end of the study, the data of only 134 women could be analyzed because 13 cases were excluded, and the actual power was post hoc calculated as 88%. Statistical analysis was performed with Statistical Program for Social Sciences (version 11.5; SPSS Inc., Chicago, IL). Before the statistical analyses were done, the distribution of the data were tested with the Shapiro-Wilk normality test. All data had normal distribution. We used c2 testing to compare categorical variables. One-way analysis of variance was used to com-
Journal of Minimally Invasive Gynecology, Vol 19, No 3, May/June 2012
pare continuous variables. The correlations between the variables were analyzed by use of the Pearson Correlation test. A p value ,.05 was considered statistically significant. Results One-hundred thirty-four sets of data were included in the analysis. The mean age and weight of participants were 58.5 6 8.1 (95% CI 57.1–59.9) years and 75.8 6 8.2 (95% CI 74.4–77.2) kg, respectively. More than 60% of the subjects (n 5 81) were at least 5 years, and about 40% were at least 10 years postmenopause. Postmenopause is described in the years, following the point in time, when permanent cessation of menstruation occurred. Mean gravidity and parity of participants were 3.8 6 2.6 and 2.6 6 1.7, respectively. Approximately two thirds (62.7%, n 5 84) of the cases reported at least monthly sexual intercourse. More than 70% (n 5 96) of participants reported painful intercourse, and 27 (20.1%) of them had vaginal inflammation (either infective or atrophic). Twenty-four (17.9%) participants had diabetes mellitus, and more than 10% had had previous gynecologic operations (n 5 18) and a history of smoking (n 5 17). Among sexually active women, painful sexual intercourse was associated with younger age, diabetic status, lower body weight, and the presence of vaginal infection. There was no statistically significant difference between the EMLA, lubricant gel, and control groups in terms of age, weight, gravidity, parity, dyspareunia, duration of menopause, sexual activity, smoking habit, diabetes mellitus, and previous vaginal and other gynecologic procedures (p . .05). Estimated mean serum FSH and estradiol levels of participants were 78.2 6 28.7 (95% CI 73.3–83.1) IU/mL and 12.8 6 15 pg/dl, respectively, and the mean vaginal length was 8.3 6 2.1 (95% CI 7.9–8.7) cm. All 3 groups were found to be similar with respect to vaginal length and serum FSH and estradiol levels (p . .05). The vaginal length of the participant was strongly correlated with duration of menopause, estrogen status, sexual activity, and body weight (p , .05) but did not correlate with age (p . .05). The pain score during the insertion of the speculum was significantly lower in the EMLA group than in both the lubricant gel and the control groups (p , .001). The highest pain score during speculum application was obtained during speculum bill opening (dilation) (Fig. 1). The pain score for the EMLA group at this time point was lower than that of the other groups (p , .001) (Table 1). Similar to the first 2 pain assessments, the pain score obtained at the final phase of the speculum examination was significantly lower in the EMLA group than in the other groups (p , .001). Comparing the lubricant gel and the control groups, a lower pain score was observed in the gel group, apart from the dilation phase of the examination (p , .001) (Table 1). The pain perceived during speculum insertion and extraction was positively correlated with the duration of menopause and negatively correlated with vaginal length and sexual activity (p , .001).
Keskin et al.
Anesthetic Cream Application Before Speculum Examination in Postmenopausal Women
Fig. 1 The visual analog scale pain scores for the 3 phases of speculum examination.
The pain perceived during dilation of the speculum was negatively correlated with sexual activity (p , .001) but was not correlated with vaginal length and postmenopausal duration (p . .05). One-hundred eighteen (88%) cases who received EMLA to the perineum and the vagina complained about slight burning after application in 5 minutes. Discussion Although many studies have assessed various interventions to reduce the physical and psychological distress associated with speculum examinations, after a literature search via PubMed we could not find any study that specifically investigated and offered a strategy for speculum application in postmenopausal women. This may reflect lack of awareness from the physician’s perspective that the experience
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of speculum application in postmenopausal women may be different from that of women in the reproductive phase. This study aimed first to estimate pain perceived at 3 discrete time points associated with different phases of speculum application (insertion, dilation, and extraction of the speculum) in postmenopausal women and second to evaluate the analgesic effect of EMLA cream during the procedure. Results of the study demonstrate that speculum examination was painful during all phases of the procedure and that dilation of the speculum was the most painful time point. Topical analgesia with EMLA cream was shown to be a highly effective treatment modality when compared with the control and the lubricant gel groups for all phases of the examination, including insertion, bill opening, and speculum extraction. As well as EMLA, patients who were treated with lubricant gel had less pain at all phases of speculum application, apart from the speculum dilation phase, when compared with the control group. According to Costello, a reduction of 15% is considered to be of clinical significance [18]. In our study, we obtained a greater reduction in pain scores than this percentage with both agents, although the reduction was greatest for the EMLA group. Therefore we suggest that EMLA application during speculum examination is a highly effective and acceptable treatment modality. A crucial aspect of pelvic examination is the maximization of the patient’s sense of dignity and control, proper gowning of the patient, good eye contact, and continuous communication. Various interventions to reduce the pain and anxiety associated with speculum examination have been studied. The use of alternative positions, different types of speculums, alternative foot rests, self insertion of the speculum, and different types of gowns have all
Table 1 Demographic features of the subjects and visual analog scale pain scores for the 3 phases of speculum examination
Age (years) (mean 6 SD) Weight (kg) (mean 6 SD) Gravida (mean 6 SD) Parity (mean 6 SD) Sexual activity Smoking Dyspareunia FSH (IU/mL) Estradiol (pg/dL) Diabetes mellitus Hysterectomy with and without oophorectomy Duration of menopause (years) (mean 6 SD) Vaginal length (cm) (mean 6 SD) Vaginal inflammation (n) Atrophic vaginitis (n) Infective vaginitis (n) VAS 1 (insertion) VAS 2 (dilation) VAS 3 (extraction)
EMLA (n 5 45)
Gel (n 5 45)
Control (n 5 44)
58.1 6 8.2 76.1 6 6.8 4.1 6 3.1 2.9 6 2.2 30 (66.6%) 7 (15.5%) 22 (76.6) 79.3 6 28.1 11.1 6 6.4 9 (20%) 7 (15%) 10.2 6 6.2 7.9 6 2.2 8 (17%) 7 1 0.4 6 0.6 2.4 6 1.6 0.9 6 1.1
59.9 6 6.7 78.6 6 8.5 3.4 6 2.3 2.2 6 1.1 24 (53.3%) 5 (11.1%) 19 (79.1%) 79.3 6 30.4 11.1 6 6.8 7 (15%) 6 (13%) 11.1 6 8.1 8.1 6 1.8 12 (26%) 9 3 1.9 6 1.2 4.3 6 2.2 1.6 6 1.2
57.6 6 9.5 72.9 6 9.3 4.1 6 2.4 2.7 6 1.9 30 (68.1%) 5 (11.3%) 21 (70.0%) 76.2 6 27.8 16.4 6 31.8 8 (18%) 5 (11%) 9.3 6 8.4 7.7 6 2.1 7 (15%) 6 1 3.5 6 2.5 6.1 6 2.3 3.0 6 2.6
p Value .24 .37 .31 .08 .29 .73 .77 .82 .30 .88 .73 .54 .11 .39
,.001 ,.001 ,.001
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demonstrated varying degrees of improvement in pain, embarrassment, and anxiety [19]. Despite the fact that local anesthetic agents have been used for different gynecologic indications involving genital mucosa, their effectiveness during speculum application to either premenopausal or postmenopausal women has not been studied [6]. Wong et al [11] investigated the effects of topical lignocaine (lidocaine was known as lignocaine in the United Kingdom) gel for pain relief in colposcopic assessment and biopsy. As part of the examination, pain scores during speculum insertion were obtained, and the authors concluded that topical lidocaine may be beneficial for a subgroup of women with a history of a previous unpleasant experience during speculum examination [11]. Liberty et al [14] evaluated analgesic efficacy of EMLA cream during hysterosalpingography and reported that the mean pain scores observed at speculum application were similar in the placebo and the EMLA-treated groups. The pain perceived during speculum insertion and extraction was positively correlated with the duration of menopause and negatively correlated with vaginal length and sexual activity. We hypothesize that the mechanism of pain perceived during insertion and extraction of the speculum arises from friction of the vaginal mucosa with the speculum, which is increased under atrophic and inflammatory conditions. The application of both EMLA and lubricant gel relieved the pain perceived during these phases. We speculate that lubricant gel is effective because of a decrease in friction between the speculum and the atrophic vagina after application and that EMLA is effective as a result of either its lubricant effect or its nerve ending–blocking effect. The pain perceived during dilation of the speculum was negatively correlated with sexual activity but not correlated with vaginal length and the duration of the menopause. Pain perceived during this phase was relieved by EMLA, and lower pain scores were obtained in the lubricant gel group than in the control group, although the difference was not statistically significant. We speculate that pain perceived during dilation of the speculum arises from both the mucosa and the pelvic floor muscles. EMLA is effective during the dilation phase because of its effect on both mucosal and muscle pain. On the other hand, lubricant gel is insufficient because it has an effect only on the mucosa. EMLA cream has a very favorable tolerability profile. The most frequent adverse events are local skin reactions (56%) that occur after the EMLA cream application to skin or mucosa [16]. However, their rates have been reported in different proportions. The local reactions include the development of burning sensation (10%–13.5%), erythema (10%–67%), pallor 1.7%, edema (6.7%–33%), and pruritis (4%) [8,9,16,20]. A slight or moderate burning sensation is experienced in the first minute of application [21]. The local reactions are generally mild and resolve spontaneously within 1 to 2 hours after removing the cream [8,16]. Proper dosing of EMLA cream is very important because systemic absorption is inherent in the nature of percutaneous
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absorption. EMLA cream, when applied to normal intact skin in excessive doses, can cause significant systemic absorption and subsequent side effects. The size of the surface area, the duration of application, the size of the patient, the condition of the skin, and impaired hepatic, renal, or cardiac function all determine the extent of side effects [20]. On the other hand, no sign of systemic reactions were observed in any studies, in which EMLA cream is used at a dose of 5 to 10 g [8,9,21,22]. Prilocaine toxicity may result in the development of methemoglobinemia, especially in infants who are receiving treatment with methemoglobin-inducing drugs [7,20]. In our study, in 88% of subjects, a burning sensation developed. The investigation of the side effects was not one of our endpoints; nevertheless, we would like to give this rate because it attracted our attention. In addition, no systemic reaction was observed in any of the cases. In conclusion, topical application of EMLA 5% cream on the perineum and the vagina of postmenopausal women before vaginal examination significantly reduces pain associated with this procedure. Although this study was conducted after calculating the minimum sample size statistically, the number of the cases can be considered few. Another weakness of our trial was that actual power was determined to be 88%. Further investigation with more samples is required to prove the effect of topical anesthetics on pain perception during speculum examination. References 1. Wright D, Fenwick J, Stephenson P, et al. Speculum ‘‘self-insertion’’: a pilot study. J Clin Nurs. 2005;14:1098–1111. 2. Ting AY, Blacklock AD, Smith PG. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod. 2004;71:1397–1404. 3. Huang AJ, Moore EE, Boyko EJ, et al. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause. 2010;17:121–126. 4. Van Voorhis BJ. Genitourinary symptoms in the menopausal transition. Am J Med. 2005;118(Suppl 12B):47–53. 5. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118(Suppl 12B):14–24. 6. Zilbert A. Topical anesthesia for minor gynecological procedures: a review. Obstet Gynecol Surv. 2002;57:171–178. 7. Gajraj NM, Pennant JH, Watcha MF. Eutectic mixture of local anetsthetics (EMLA) cream. Anesth Analg. 1994;78:574–583. 8. Rylander E, Sj€oberg I, Lillieborg S, et al. Local anesthesia of the genital mucosa with a lidocaine/prilocaine cream (EMLA) for laser treatment of condyloma acuminate: a placebo-controlled study. Obstet Gynecol. 1990;75:302–306. 9. Ljunghall K, Lillieborg S. Local anaesthesia with a lidocaine/prilocaine cream (EMLA) for cautery of condylomata acuminata on the vulval mucosa. The effect of timing of application of the cream. Acta Derm Venereol. 1989;69:362–365. 10. Monsonego J, Semaille C. Local anesthesia of genital mucosa with a lidocaine/prilocaine combination cream before laser therapy of human papillomavirus lesions. Eur J Dermatol. 2000;10:607–610. 11. Wong GC, Li RH, Wong TS, et al. The effect of topical lignocaine gel in pain relief for colposcopic assessment and biopsy: is it useful? BJOG. 2008;115:1057–1060. 12. Sarkar PK. Topical anaesthesia with lignocaine-prilocaine cream (EMLA) for carbon dioxide treatment to the cervix–a pilot study. Br J Clin Pract. 1990;44:352–353.
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Anesthetic Cream Application Before Speculum Examination in Postmenopausal Women
13. Stigliano CM, Mollo A, Zullo F. Two modalities of topical anesthesia for office hysteroscopy. Int J Gynaecol Obstet. 1997;59:151–152. 14. Liberty G, Gal M, Halevy-Shalem T, et al. Lidocaine-prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study. Hum Reprod. 2007;22: 1335–1339. 15. Wahlgren CF, Lillieborg S. Split-skin grafting with lidocaineprilocaine cream: a meta-analysis of efficacy and safety in geriatric versus nongeriatric patients. Plast Reconstr Surg. 2001;107: 750–756. 16. Buckley MM, Benfield P. Eutectic lidocaine/prilocaine cream. A review of the topical anaesthetic/analgesic efficacy of a eutectic mixture of local anaesthetics (EMLA). Drugs. 1993;46:126–151. 17. Kaweski S. Plastic Surgery Educational Foundation Technology Assessment Committee. Topical anesthetic creams. Plast Reconstr Surg. 2008;121:2161–2165.
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18. Costello MF, Horrowitz S, Steigrad S, et al. Transcervical intrauterine topical local anesthetic at hysterosalpingography: a prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril. 2002; 78:1116–11122. 19. Seehusen DA, Johnson DR, Earwood JS, et al. Improving women’s experience during speculum examinations at routine gynaecological visits: randomised clinical trial. BMJ. 2006;333:171. 20. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol. 2001; 44:399–400. 21. Stymne B, Lillieborg S. Plasma concentrations of lignocaine and prilocaine after a 24-h application of analgesic cream (EMLA) to leg ulcers. Br J Dermatol. 2001;145:530–534. 22. van der Burght M, Schønemann NK, Laursen JK, et al. Duration of analgesia following application of eutectic mixture of local anaesthetics (EMLA) on genital mucosa. Acta Derm Venereol. 1993;73:456–458.
Topical Anesthetic (Lidocaine-Prilocaine) Cream Application Before Speculum Examination in Postmenopausal Women Aktepe Esra Keskin, MD*, Yuksel Onaran, MD, Iltemur Candan Duvan, MD, Serap Simavli, MD, and Hasan Kafali, MD From the Department of Obstetrics and Gynecology, Fatih University Medical School, Ankara, Turkey (all authors).
ABSTRACT Study Objective: To evaluate the effectiveness of lidocaine–prilocaine (EMLA 5%) cream application to genital mucosa for reducing pain or discomfort associated with speculum examination in postmenopausal women. Design: A randomized controlled study (Canadian Task Force classification I). Setting: A university hospital. Patients: One-hundred thirty-four postmenopausal women. Interventions: The subjects were randomized to an EMLA cream group, a lubricant gel group, or a control group. General data was collected, including age, body weight, gravidity, parity, smoking habits, history of diabetes mellitus, previous gynecologic operations, dyspareunia, sexual activity, and duration of menopause. All patients were asked to score pain at 3 time points (insertion, dilation, and extraction of speculum) during the procedure using a visual analog scale. Pain intensity during speculum examination was compared between the groups. Measurements and Main Results: There was no statistically significant difference between the EMLA cream, the lubricant gel, and the control groups in terms of age, weight, gravidity, parity, dyspareunia, duration of menopause, sexual activity, smoking habit, diabetes mellitus, previous vaginal and other gynecological procedures, vaginal length, and serum folliclestimulating hormone and estradiol levels (p . .05). The pain scores obtained during all phases of speculum application were significantly lower in the EMLA group than in both the lubricant gel and the control groups (p , .001). Comparing the gel and the control groups, a lower pain score was observed in the former, except for the second phase of the examination (p , .001). Conclusion: Topical application of EMLA 5% cream on genital mucosa of postmenopausal women before vaginal examination significantly reduces pain associated with speculum application. Journal of Minimally Invasive Gynecology (2012) 19, 350–355 Ó 2012 AAGL. All rights reserved. Keywords:
DISCUSS
Topical anesthetic; Lidocaine; Prilocaine; Speculum examination; Postmenopause
You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-19-3-11-00446
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
Pelvic examination, an important part of preventive health care for adult women, is performed to help detect certain cancers in their early stages, infections, or other reproductive system problems. Despite its importance, many women are reluctant and anxious about the procedure beThe authors declare that they have no conflict of interest. Corresponding author: Aktepe Esra Keskin, MD, Birlik mah. 450. cad. 499. sok. No: 3/5 C ¸ ankaya, 06610 Ankara, Turkey. E-mail: [email protected] Submitted October 13, 2011. Accepted for publication January 5, 2012. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2012 AAGL. All rights reserved. doi:10.1016/j.jmig.2012.01.005
cause of potential embarrassment, apprehension, and fear, as well as discomfort and pain [1]. The female genital mucous membrane is highly sensitive to pain, which is increased in the presence of atrophy and inflammation [2]. Because estrogen levels decrease at menopause, women often experience a variety of adverse vaginal symptoms, including dryness, loss of tone, irritation, hyperalgesia, and pain, which may be exacerbated during intercourse and vaginal examination [2–4]. These symptoms are generally attributed to declining estrogen levels, which result in an increase in a subset of vaginal sensory nerve endings and in profound atrophic and inflammatory changes in vaginal
Keskin et al.
Anesthetic Cream Application Before Speculum Examination in Postmenopausal Women
tissue [2]. Therefore speculum application is even more anxiety-provoking and difficult during the postmenopausal period [5]. Topical anesthetics have been extensively studied in adults and children for a range of needle procedures, including vaccination, intravenous cannulation, venipuncture, and dermatologic procedures, such as split-skin grafting and removal of genital warts [6]. A number of topical anesthetics have been investigated for different indications involving the genital mucosa, including Eutectic Mixture of Local Anaesthetics (EMLA) 5% cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), benzocaine 20% gel, cocaine spray, 2% mepivacaine, 2% lidocaine gel, and 1% tetracaine [6]. EMLA cream is an oil-in-water emulsion of 2.5% lidocaine and 2.5% prilocaine that optimizes the absorption through intact skin. EMLA penetrates a mucosal surface faster than keratinized epithelium on female genitourinary mucosa [7]. EMLA cream provided the most effective degree of anesthesia after 5 to 10 minutes of application time on the genital mucosa [8,9]. The quality of analgesia decreases with application times longer than 10 to 15 minutes [8,9]. The female genital mucous membrane is highly sensitive to pain. Eutectic lidocaine/prilocaine cream is a formulation of local anesthetics that has proven to be effective and well tolerated in the relief of pain associated with various minor gynecologic interventions [6]. Procedures for which local anesthetics and analgesics are appropriate include removal of genital warts by laser surgery [8,10], thermocautery, or cryotherapy [9]; colposcopic assessment; vaginal, vulvar, cervical, and endocervical biopsies [11]; laser treatment of preinvasive cervical lesions [12]; hysteroscopy [13]; and hysterosalpingography [14]. Because these procedures are relatively superficial, topical anesthesia is a logical option with respect to these procedures and avoids the risks associated with other methods of anesthesia. However, to date, the application of a topical anesthetic during speculum examination has not been studied. EMLA cream has been shown to be safe and efficacious in geriatric patients, but its use is controversial in neonates [15–17]. The aim of this randomized controlled study was to estimate the effectiveness of EMLA cream application to the genital mucosa for pain or discomfort associated with speculum examination in postmenopausal women. Materials and Methods A total of 147 postmenopausal women, aged between 55 and 65 years and not taking hormone therapy for at least 3 months or ingesting prescription or nonprescription herbal medications, were recruited into the study. All candidates gave written informed consent before study entry. Postmenopausal status was determined by menstrual cycle history, as well as follicle-stimulating hormone (FSH)
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(.25 mIU/mL) and estradiol (,25 pg/mL) levels at time of entry into the study. Women with known hypersensitivity to local anesthetics or to oral analgesics were excluded. A complete physical examination and medical history were obtained from all study participants. General data, such as age, body weight, gravidity, parity, smoking habit, history of diabetes mellitus, previous gynecologic operation, dyspareunia, sexual activity (1 or more times per month was accepted as sexually active), and duration of menopause, was collected. Subjects were assigned randomly to receive lidocaine 25 mg plus prilocaine 25 mg/g cream (EMLA, AstraZeneca, Wilmingston, DE); lubricant gel (Ty & Ja; Dr. M€uller Pharma, Hradec Kralove, Czech Republic), a fluid and semisolid gel with high content of water and containing hydroxyethylcellulose; or to a control group. The randomization sequence that was used in this trial was generated by a computerized random-number generator. The allocation was concealed until the results were statistically evaluated. A total of 48 women were randomized to the EMLA cream group, 46 to the lubricant gel group, and 53 to the control group. During the procedure, 13 subjects were excluded from the study for the following reasons: 2 (1 from lubricant gel group and 1 from control) had passed urine after the application of gel; 4 (1 from the EMLA group, 3 from the control group) did not tolerate the procedure just at the initial point, before the agents were applied, or the speculum was inserted (the cases did not give permission to apply the agents or insert the speculum when they were still in the lithotomy position, and in those cases the pain intensity could not be assessed); 4 (one from the EMLA group, 3 from the control group) were removed because of lack of cooperation; and 3 (1 from the EMLA group, 2 from the control group) had additional procedures carried out other than a vaginal examination (1 had a cervical polyp removed, and 2 had endometrial sampling performed). All patients enrolled in the study were asked to score the pain at 3 time points during the procedure using a Visual Analog Scale (VAS). The VAS consisted of a 10-cm–long straight line, scaled from 0 to 10 (0 5 no pain and 10 5 severe pain) without numerical values on the scale, except for ‘‘0’’ at the initial and ‘‘10’’ in the end. Patients were asked to specify the point that represents their level of perceived pain intensity. After the subjects had marked for each pain on the scale, the distance of the points from ‘‘0’’ point was measured with a ruler and recorded. A detailed explanation of the VAS and its application was delivered personally to each woman before the procedure. All patients were examined in the lithotomy position at 30- to 45-degree angles to the examination table. All women were draped with a full-sized sheet in a standardized manner that maximized coverage of the woman and allowed visualization of the perineum. A sterile, bivalve, medium-sized Grave’s disposable plastic speculum of a standard size with dimensions 90 ! 23 mm and an external light source were used for all examinations.
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In the EMLA group, EMLA cream 5 g was applied to the perineum and vaginal orifice and introduced as deeply as possible with the physician’s finger. The commercial type of EMLA cream is available and marketed in 5-g amounts in small tubes that are suitable for single use. For this reason, we decided to use this amount for both agents to be able to fix the standardization. The speculum examination followed 5 minutes later. In the lubricant gel group, the same procedure was performed with same amount of gel. The agents were applied by 5 physicians, and the mean length of their index fingers was 7.1 6 0.7 cm. In the control group nothing was applied to the perineum or to the vagina. For all patients, speculum insertion was performed as follows. The speculum was warmed, and patients were informed about what was going to happen. The labia were spread from below to introduce the speculum, which was inserted at a 45-degree angle pointing downward then rotated horizontally as the insertion continued. A VAS score (insertion) was obtained at this point. Next, the bill of the speculum was opened up until the cervix could be seen, and the speculum was secured by turning the thumbnut. A second VAS score (dilation) was recorded. During speculum examination, the specimens (cervical smear with cervical brush and cervicovaginal culture with a swab) were obtained for pathologic and microbiologic assessment, and vaginal length was measured with a ruler. The speculum was withdrawn slightly, which allowed the bill to close together, and at this stage (extraction) the final VAS score was obtained. At each stage of the procedures, VAS scores were recorded in real time by the same medical observer (S.S.) blinded to the randomization. The observer joined the study just before the speculum was inserted. She did not have any knowledge about whether any agent was applied to the cases. Before the study was carried out, a total sample size of 138 subjects (46 cases per groups) was calculated to conform to the following statistical requirement: effect size (f) 40% difference between groups with decreasing pain intensity according to VAS, type I error (a) 5 .05, type II error (b) 5 .10, and power 5 90%. The effect size was determined according to the results of the pilot trial performed on the 15 cases (5 cases for each group) before the study was constructed. Because the pain intensity is perceived the most during the dilation stage, the pain intensities of this stage were considered the reference intensity to find the difference between the groups with an agent (EMLA or lubricant gel) and the control group. A 40% difference between the VAS score means of the groups was considered clinically significant. However, at the end of the study, the data of only 134 women could be analyzed because 13 cases were excluded, and the actual power was post hoc calculated as 88%. Statistical analysis was performed with Statistical Program for Social Sciences (version 11.5; SPSS Inc., Chicago, IL). Before the statistical analyses were done, the distribution of the data were tested with the Shapiro-Wilk normality test. All data had normal distribution. We used c2 testing to compare categorical variables. One-way analysis of variance was used to com-
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pare continuous variables. The correlations between the variables were analyzed by use of the Pearson Correlation test. A p value ,.05 was considered statistically significant. Results One-hundred thirty-four sets of data were included in the analysis. The mean age and weight of participants were 58.5 6 8.1 (95% CI 57.1–59.9) years and 75.8 6 8.2 (95% CI 74.4–77.2) kg, respectively. More than 60% of the subjects (n 5 81) were at least 5 years, and about 40% were at least 10 years postmenopause. Postmenopause is described in the years, following the point in time, when permanent cessation of menstruation occurred. Mean gravidity and parity of participants were 3.8 6 2.6 and 2.6 6 1.7, respectively. Approximately two thirds (62.7%, n 5 84) of the cases reported at least monthly sexual intercourse. More than 70% (n 5 96) of participants reported painful intercourse, and 27 (20.1%) of them had vaginal inflammation (either infective or atrophic). Twenty-four (17.9%) participants had diabetes mellitus, and more than 10% had had previous gynecologic operations (n 5 18) and a history of smoking (n 5 17). Among sexually active women, painful sexual intercourse was associated with younger age, diabetic status, lower body weight, and the presence of vaginal infection. There was no statistically significant difference between the EMLA, lubricant gel, and control groups in terms of age, weight, gravidity, parity, dyspareunia, duration of menopause, sexual activity, smoking habit, diabetes mellitus, and previous vaginal and other gynecologic procedures (p . .05). Estimated mean serum FSH and estradiol levels of participants were 78.2 6 28.7 (95% CI 73.3–83.1) IU/mL and 12.8 6 15 pg/dl, respectively, and the mean vaginal length was 8.3 6 2.1 (95% CI 7.9–8.7) cm. All 3 groups were found to be similar with respect to vaginal length and serum FSH and estradiol levels (p . .05). The vaginal length of the participant was strongly correlated with duration of menopause, estrogen status, sexual activity, and body weight (p , .05) but did not correlate with age (p . .05). The pain score during the insertion of the speculum was significantly lower in the EMLA group than in both the lubricant gel and the control groups (p , .001). The highest pain score during speculum application was obtained during speculum bill opening (dilation) (Fig. 1). The pain score for the EMLA group at this time point was lower than that of the other groups (p , .001) (Table 1). Similar to the first 2 pain assessments, the pain score obtained at the final phase of the speculum examination was significantly lower in the EMLA group than in the other groups (p , .001). Comparing the lubricant gel and the control groups, a lower pain score was observed in the gel group, apart from the dilation phase of the examination (p , .001) (Table 1). The pain perceived during speculum insertion and extraction was positively correlated with the duration of menopause and negatively correlated with vaginal length and sexual activity (p , .001).
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Anesthetic Cream Application Before Speculum Examination in Postmenopausal Women
Fig. 1 The visual analog scale pain scores for the 3 phases of speculum examination.
The pain perceived during dilation of the speculum was negatively correlated with sexual activity (p , .001) but was not correlated with vaginal length and postmenopausal duration (p . .05). One-hundred eighteen (88%) cases who received EMLA to the perineum and the vagina complained about slight burning after application in 5 minutes. Discussion Although many studies have assessed various interventions to reduce the physical and psychological distress associated with speculum examinations, after a literature search via PubMed we could not find any study that specifically investigated and offered a strategy for speculum application in postmenopausal women. This may reflect lack of awareness from the physician’s perspective that the experience
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of speculum application in postmenopausal women may be different from that of women in the reproductive phase. This study aimed first to estimate pain perceived at 3 discrete time points associated with different phases of speculum application (insertion, dilation, and extraction of the speculum) in postmenopausal women and second to evaluate the analgesic effect of EMLA cream during the procedure. Results of the study demonstrate that speculum examination was painful during all phases of the procedure and that dilation of the speculum was the most painful time point. Topical analgesia with EMLA cream was shown to be a highly effective treatment modality when compared with the control and the lubricant gel groups for all phases of the examination, including insertion, bill opening, and speculum extraction. As well as EMLA, patients who were treated with lubricant gel had less pain at all phases of speculum application, apart from the speculum dilation phase, when compared with the control group. According to Costello, a reduction of 15% is considered to be of clinical significance [18]. In our study, we obtained a greater reduction in pain scores than this percentage with both agents, although the reduction was greatest for the EMLA group. Therefore we suggest that EMLA application during speculum examination is a highly effective and acceptable treatment modality. A crucial aspect of pelvic examination is the maximization of the patient’s sense of dignity and control, proper gowning of the patient, good eye contact, and continuous communication. Various interventions to reduce the pain and anxiety associated with speculum examination have been studied. The use of alternative positions, different types of speculums, alternative foot rests, self insertion of the speculum, and different types of gowns have all
Table 1 Demographic features of the subjects and visual analog scale pain scores for the 3 phases of speculum examination
Age (years) (mean 6 SD) Weight (kg) (mean 6 SD) Gravida (mean 6 SD) Parity (mean 6 SD) Sexual activity Smoking Dyspareunia FSH (IU/mL) Estradiol (pg/dL) Diabetes mellitus Hysterectomy with and without oophorectomy Duration of menopause (years) (mean 6 SD) Vaginal length (cm) (mean 6 SD) Vaginal inflammation (n) Atrophic vaginitis (n) Infective vaginitis (n) VAS 1 (insertion) VAS 2 (dilation) VAS 3 (extraction)
EMLA (n 5 45)
Gel (n 5 45)
Control (n 5 44)
58.1 6 8.2 76.1 6 6.8 4.1 6 3.1 2.9 6 2.2 30 (66.6%) 7 (15.5%) 22 (76.6) 79.3 6 28.1 11.1 6 6.4 9 (20%) 7 (15%) 10.2 6 6.2 7.9 6 2.2 8 (17%) 7 1 0.4 6 0.6 2.4 6 1.6 0.9 6 1.1
59.9 6 6.7 78.6 6 8.5 3.4 6 2.3 2.2 6 1.1 24 (53.3%) 5 (11.1%) 19 (79.1%) 79.3 6 30.4 11.1 6 6.8 7 (15%) 6 (13%) 11.1 6 8.1 8.1 6 1.8 12 (26%) 9 3 1.9 6 1.2 4.3 6 2.2 1.6 6 1.2
57.6 6 9.5 72.9 6 9.3 4.1 6 2.4 2.7 6 1.9 30 (68.1%) 5 (11.3%) 21 (70.0%) 76.2 6 27.8 16.4 6 31.8 8 (18%) 5 (11%) 9.3 6 8.4 7.7 6 2.1 7 (15%) 6 1 3.5 6 2.5 6.1 6 2.3 3.0 6 2.6
p Value .24 .37 .31 .08 .29 .73 .77 .82 .30 .88 .73 .54 .11 .39
,.001 ,.001 ,.001
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demonstrated varying degrees of improvement in pain, embarrassment, and anxiety [19]. Despite the fact that local anesthetic agents have been used for different gynecologic indications involving genital mucosa, their effectiveness during speculum application to either premenopausal or postmenopausal women has not been studied [6]. Wong et al [11] investigated the effects of topical lignocaine (lidocaine was known as lignocaine in the United Kingdom) gel for pain relief in colposcopic assessment and biopsy. As part of the examination, pain scores during speculum insertion were obtained, and the authors concluded that topical lidocaine may be beneficial for a subgroup of women with a history of a previous unpleasant experience during speculum examination [11]. Liberty et al [14] evaluated analgesic efficacy of EMLA cream during hysterosalpingography and reported that the mean pain scores observed at speculum application were similar in the placebo and the EMLA-treated groups. The pain perceived during speculum insertion and extraction was positively correlated with the duration of menopause and negatively correlated with vaginal length and sexual activity. We hypothesize that the mechanism of pain perceived during insertion and extraction of the speculum arises from friction of the vaginal mucosa with the speculum, which is increased under atrophic and inflammatory conditions. The application of both EMLA and lubricant gel relieved the pain perceived during these phases. We speculate that lubricant gel is effective because of a decrease in friction between the speculum and the atrophic vagina after application and that EMLA is effective as a result of either its lubricant effect or its nerve ending–blocking effect. The pain perceived during dilation of the speculum was negatively correlated with sexual activity but not correlated with vaginal length and the duration of the menopause. Pain perceived during this phase was relieved by EMLA, and lower pain scores were obtained in the lubricant gel group than in the control group, although the difference was not statistically significant. We speculate that pain perceived during dilation of the speculum arises from both the mucosa and the pelvic floor muscles. EMLA is effective during the dilation phase because of its effect on both mucosal and muscle pain. On the other hand, lubricant gel is insufficient because it has an effect only on the mucosa. EMLA cream has a very favorable tolerability profile. The most frequent adverse events are local skin reactions (56%) that occur after the EMLA cream application to skin or mucosa [16]. However, their rates have been reported in different proportions. The local reactions include the development of burning sensation (10%–13.5%), erythema (10%–67%), pallor 1.7%, edema (6.7%–33%), and pruritis (4%) [8,9,16,20]. A slight or moderate burning sensation is experienced in the first minute of application [21]. The local reactions are generally mild and resolve spontaneously within 1 to 2 hours after removing the cream [8,16]. Proper dosing of EMLA cream is very important because systemic absorption is inherent in the nature of percutaneous
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absorption. EMLA cream, when applied to normal intact skin in excessive doses, can cause significant systemic absorption and subsequent side effects. The size of the surface area, the duration of application, the size of the patient, the condition of the skin, and impaired hepatic, renal, or cardiac function all determine the extent of side effects [20]. On the other hand, no sign of systemic reactions were observed in any studies, in which EMLA cream is used at a dose of 5 to 10 g [8,9,21,22]. Prilocaine toxicity may result in the development of methemoglobinemia, especially in infants who are receiving treatment with methemoglobin-inducing drugs [7,20]. In our study, in 88% of subjects, a burning sensation developed. The investigation of the side effects was not one of our endpoints; nevertheless, we would like to give this rate because it attracted our attention. In addition, no systemic reaction was observed in any of the cases. In conclusion, topical application of EMLA 5% cream on the perineum and the vagina of postmenopausal women before vaginal examination significantly reduces pain associated with this procedure. Although this study was conducted after calculating the minimum sample size statistically, the number of the cases can be considered few. Another weakness of our trial was that actual power was determined to be 88%. Further investigation with more samples is required to prove the effect of topical anesthetics on pain perception during speculum examination. References 1. Wright D, Fenwick J, Stephenson P, et al. Speculum ‘‘self-insertion’’: a pilot study. J Clin Nurs. 2005;14:1098–1111. 2. Ting AY, Blacklock AD, Smith PG. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod. 2004;71:1397–1404. 3. Huang AJ, Moore EE, Boyko EJ, et al. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause. 2010;17:121–126. 4. Van Voorhis BJ. Genitourinary symptoms in the menopausal transition. Am J Med. 2005;118(Suppl 12B):47–53. 5. Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118(Suppl 12B):14–24. 6. Zilbert A. Topical anesthesia for minor gynecological procedures: a review. Obstet Gynecol Surv. 2002;57:171–178. 7. Gajraj NM, Pennant JH, Watcha MF. Eutectic mixture of local anetsthetics (EMLA) cream. Anesth Analg. 1994;78:574–583. 8. Rylander E, Sj€oberg I, Lillieborg S, et al. Local anesthesia of the genital mucosa with a lidocaine/prilocaine cream (EMLA) for laser treatment of condyloma acuminate: a placebo-controlled study. Obstet Gynecol. 1990;75:302–306. 9. Ljunghall K, Lillieborg S. Local anaesthesia with a lidocaine/prilocaine cream (EMLA) for cautery of condylomata acuminata on the vulval mucosa. The effect of timing of application of the cream. Acta Derm Venereol. 1989;69:362–365. 10. Monsonego J, Semaille C. Local anesthesia of genital mucosa with a lidocaine/prilocaine combination cream before laser therapy of human papillomavirus lesions. Eur J Dermatol. 2000;10:607–610. 11. Wong GC, Li RH, Wong TS, et al. The effect of topical lignocaine gel in pain relief for colposcopic assessment and biopsy: is it useful? BJOG. 2008;115:1057–1060. 12. Sarkar PK. Topical anaesthesia with lignocaine-prilocaine cream (EMLA) for carbon dioxide treatment to the cervix–a pilot study. Br J Clin Pract. 1990;44:352–353.
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13. Stigliano CM, Mollo A, Zullo F. Two modalities of topical anesthesia for office hysteroscopy. Int J Gynaecol Obstet. 1997;59:151–152. 14. Liberty G, Gal M, Halevy-Shalem T, et al. Lidocaine-prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study. Hum Reprod. 2007;22: 1335–1339. 15. Wahlgren CF, Lillieborg S. Split-skin grafting with lidocaineprilocaine cream: a meta-analysis of efficacy and safety in geriatric versus nongeriatric patients. Plast Reconstr Surg. 2001;107: 750–756. 16. Buckley MM, Benfield P. Eutectic lidocaine/prilocaine cream. A review of the topical anaesthetic/analgesic efficacy of a eutectic mixture of local anaesthetics (EMLA). Drugs. 1993;46:126–151. 17. Kaweski S. Plastic Surgery Educational Foundation Technology Assessment Committee. Topical anesthetic creams. Plast Reconstr Surg. 2008;121:2161–2165.
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18. Costello MF, Horrowitz S, Steigrad S, et al. Transcervical intrauterine topical local anesthetic at hysterosalpingography: a prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril. 2002; 78:1116–11122. 19. Seehusen DA, Johnson DR, Earwood JS, et al. Improving women’s experience during speculum examinations at routine gynaecological visits: randomised clinical trial. BMJ. 2006;333:171. 20. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol. 2001; 44:399–400. 21. Stymne B, Lillieborg S. Plasma concentrations of lignocaine and prilocaine after a 24-h application of analgesic cream (EMLA) to leg ulcers. Br J Dermatol. 2001;145:530–534. 22. van der Burght M, Schønemann NK, Laursen JK, et al. Duration of analgesia following application of eutectic mixture of local anaesthetics (EMLA) on genital mucosa. Acta Derm Venereol. 1993;73:456–458.