Reproductive BioMedicine Online (2014) xxx, xxx– xxx
www.sciencedirect.com www.rbmonline.com
ARTICLE
Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram EA Bachman a, S Senapati
a,*
, MD Sammel b, SK Kalra
a
a University of Pennsylvania, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, 3701 Market Street, Suite 800, Philadelphia, PA 19104, United States b University of Pennsylvania School of Medicine, Department of Biostatistics and Epidemiology, 3451 Walnut Street, Philadelphia, PA 19104, United States
* Corresponding author. E-mail address: [email protected] (S Senapati). Dr. Emelia A Bachman graduated from the Weill Medical College of Cornell University, USA in 2006. She then pursued her residency in obstetrics and gynaecology at the University of Maryland Medical Center (2006–2008) and the Hospital of the University of Pennsylvania (2008–2010). Dr. Bachman completed her fellowship in reproductive endocrinology and infertility at the Hospital of the University of Pennsylvania in 2013. She is a board-certified obstetrician and gynaecologist and is currently a reproductive endocrinologist at Reproductive Associates of Delaware in Newark, Delaware.
Abstract Many women experience pain during hysterosalpingogram (HSG). This prospective, randomized, double-blinded,
placebo-controlled study assessed whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, parity, pre-procedure oral analgesic use and history of dysmenorrhoea and/or chronic pelvic pain. Median change in pain score from baseline to procedure was 50.6 mm ( 7.4 to 98.8 mm) in the benzocaine group and 70.4 mm (19.8 to 100 mm) in the placebo group. There was no difference between groups after adjusting for history of dysmenorrhoea. There was no difference in resolution of pain in benzocaine versus placebo groups at 5 min post procedure – median pain score difference 11.1 ( 90.1 to 18.5) versus 37.0 ( 100 to 1.2) – or at 30 min post procedure. Satisfaction scores did not differ by treatment and did not correlate with pain score during the procedure (rho = 0.005). The use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain. RBMOnline ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: analgesia, benzocaine, HSG, hysterosalpingogram, pain relief, randomized controlled trial
http://dx.doi.org/10.1016/j.rbmo.2014.02.012 1472-6483/ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
2
Introduction Hysterosalpingogram (HSG) is an integral part of the evaluation of subfertile women, as it can be used to both evaluate intrauterine pathology and tubal patency. Poor pain control can often limit the quality of the examination. Furthermore, anticipation of pain may preclude patient acceptance of the examination and cause unnecessary anxiety. Up to 72% of women complain of pain during hysterosalpingography (Ayida et al., 1996). There is little consensus regarding the optimal management of pain during HSG. A Cochrane review of the current literature investigating pharmacological interventions for pain relief during HSG found no evidence of benefit when using pain relief medication compared with placebo both during and immediately after the procedure, but did demonstrate that there was a limited benefit 30 min after the procedure (Ahmad et al., 2007). Oral, intrauterine and topical analgesics have been evaluated for pain relief at HSG (Ahmad et al., 2007; Ayida et al., 1996; Cengiz et al., 2006; Costello et al., 2002, 2005; Elson and Ridley, 2000; Frishman et al., 2004; Kafali et al., 2003; Liberty et al., 2007; Lorino et al., 1990; Owens et al., 1985; Peters et al., 1996; Robinson et al., 2007). Application of 20% benzocaine gel to the cervix has been shown to provide significant relief during HSG in one study (Lorino et al., 1990) while another suggested that application of lidocaine to the uterine cervix significantly reduces pain at the time of cervical instrumentation, but not during uterine filling and spillage (Robinson et al., 2007). However, interpretation of the current literature is limited by lack of blinding, placebo control, randomization and unclear allocation. Only two of the eight studies included in the Cochrane review performed a power calculation. In addition, the pain scales used were not always reliable and valid. Also, in cases where the pain scores were significantly different when compared with placebo, patient satisfaction was not always assessed. Given these limitations in the literature, there is currently no consensus on the optimal analgesic regimen during HSG. This work performed a randomized, double-blinded, placebo-controlled investigation to address these limitations. The primary objective was to assess if benzocaine spray was associated with greater pain relief during after HSG compared with placebo. The secondary objective was to assess if the use of benzocaine spray was associated with greater patient satisfaction after HSG.
EA Bachman et al. procedure in this practice, pre-procedure ibuprofen was recommended. Informed consent was obtained on the day of HSG. Patients who consented were randomized to either benzocaine or saline placebo spray. Randomization was performed by the Investigational Drug Service at the Hospital of the University of Pennsylvania via a computer-generated random-number sequence in blocks of four. Drug canisters were blinded to both patient and clinician. All hysterosalpingograms were performed in a single centre by the same group of physicians in a similar fashion. The hysterosalpingogram was performed with the patient in modified dorsal lithotomy position. A sterile speculum was placed by the provider and the cervix cleansed with chlorhexidine solution. Benzocaine or placebo saline was sprayed on the anterior lip of the cervix prior to application of a single-tooth tenaculum. The acorn cannula was inserted into the cervix. Approximately 5–10 ml water-soluble contrast dye was injected under fluoroscopy. Pain scores were obtained using a validated visual analogue scale (DeLoach et al., 1998) pre-procedure, immediately after HSG (designated as time 0) and at 5 and 30 min post procedure. Satisfaction was assessed at 30 min post procedure. Satisfaction was measured using a validated satisfaction survey (Barnhart et al., 2007) on a 5-point scale, 1 representing least satisfied and 5 extremely satisfied. The primary outcome was defined as the difference in pain score from pre-procedure to procedure (time 0). Secondary outcomes included pain resolution (time 0 to time 5, and time 0 to time 30) and patient satisfaction.
Statistical analysis An a priori sample size calculation determined at least 28 patients were needed to detect a clinically significant 13 mm difference in pain score (a = 0.05, power = 0.80) with a standard deviation of 12 mm. Intention-to-treat analysis was performed. t-Test or Fisher’s exact test was used to evaluate differences in risk factors. Differences in the median change in pain scores were assessed using Wilcoxon rank-sum test. Fisher’s exact test was used to assess differences in satisfaction scores by treatment group. Correlation between pain and satisfaction scores was assessed by Spearman’s correlation coefficient. To analyse the change in pain score over time, a random-effects linear regression model was used to account for each individual’s baseline in pain scores. STATA statistical software version 12.0 (StatCorp, College Station, TX, USA) was used for all statistical analyses.
Materials and methods Results This randomized, double-blinded, placebo-controlled trial was conducted from December 2011 to April 2012 at the University of Pennsylvania after approval was obtained from the Institutional Review Board (protocol no. 809399, approved 15 December 2011). All women over the age of 18 who had been referred for hysterosalpingography during this period were deemed eligible. All patients scheduled for HSG at the institution were contacted to enrol in the study. Patients were excluded if they had a positive pregnancy test on the day of HSG or if they reported a hypersensitivity to benzocaine or related analgesic agents. As per routine
Thirty women consented the day of procedure (Figure 1). Only 29 patients received either benzocaine or placebo saline spray due to a single canister malfunction. Fifteen patients were analysed in the placebo group and 15 in the benzocaine group. The baseline characteristics were not statistically different between both groups. Patients were similar in age, race, parity, history of dysmenorrhoea and history of chronic pelvic pain (Table 1). Additionally, there was no difference in the groups with respect to the use of pre-procedure ibuprofen or other oral medication.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
Pain relief at hysterosalpingogram
3 100.0
Assessed for eligibility (n = 47)
90.0
Enrollment
Not meeting inclusion criteria (n = 0) Declined to participate (n = 17)
Pain score (mm)
80.0 Excluded (n = 17)
70.0 60.0 50.0 Benzocaine
40.0
Placebo
30.0 20.0 10.0
Randomized (n = 30)
0.0
Analysis
Follow-up
Allocation
Time (min) Allocated to benzocaine (n = 15) Received allocated intervention (n = 14) Did not receive allocated intervention (n = 1) (due to canister malfunction)
Allocated to placebo (n = 15) Received allocated placebo (n = 15) Did not receive allocated placebo (n = 0)
Lost to follow-up (n = 0) Discontinued intervention (n = 0)
Lost to follow-up (n = 0) Discontinued intervention (n = 0)
Analysed (n = 15) Excluded from analysis (n = 0)
Figure 1
Analysed (n = 15) Excluded from analysis (n = 0)
CONSORT flow diagram.
(One patient in the placebo group and two in the benzocaine group took acetaminophen due to an allergy). When comparing the results of HSG, there were no differences in the proportion of patients with unilateral or bilateral tubal obstruction between the two groups. No patients had uterine anomalies. The median change in pain score from baseline to immediately post procedure was not significantly different
Table 1
Figure 2
Median pain scores. Values are median and range.
between the benzocaine and placebo groups (Figure 2). The differences in pain scores were median (range) 50.6 mm ( 7.4 to 98.8 mm) in the benzocaine group and 70.4 mm (19.8 to 100 mm) in the placebo group. Resolution of pain at 5 min post procedure was not different between the two groups. The pain score difference at this time point was 11.1 ( 90.1 to 18.5) in the benzocaine group and 37.0 ( 100 to 1.2) in the placebo group. At 30 min post procedure, there was no difference in resolution of pain from baseline (Table 2). Even after adjusting for a history of dysmenorrhoea or chronic pelvic pain, these scores were not impacted. When evaluating satisfaction scores, all patients reported being ‘satisfied’, ‘highly satisfied’ or ‘extremely satisfied’ (Table 3). The majority of patients reported being ‘extremely satisfied’ in both groups (71.4% versus 71.4%). Patient satisfaction did not correlate with pain score during the procedure (rho = 0.005). Table 2
Median changes in pain score.
Time interval
Benzocaine (mm)
Placebo (mm)
Baseline–time 0 Time 0–time 5
50.6 ( 7.4 to 98.8)
70.4 (19.8 to 100)
Baseline characteristics.
x Age (years) Racea Caucasian Black Asian Nulligravid Nulliparous History of dysmenorrhoea History of chronic pelvic pain Premedication Bilateral obstruction Unilateral obstruction
Benzocaine (n = 15)
Placebo (n = 15)
34.3 ± 4.8 xxx 8 (53.3) 5 (33.3) 1 (6.7) 7 (46.7) 12 (80.0) 7 (46.7)
33.3 ± 6.5
2 (13.3)
2 (13.3)
Table 3
15 (100) 2 (13.3) 4 (26.7)
13 (86.7) 1 (6.7) 3 (20.0)
Satisfaction score
Benzocaine (n = 14)
Placebo (n = 14)
3 4 5
2 (14.3) 2 (14.3) 10 (71.4)
0 (0) 4 (28.6) 10 (71.4)
6 (40.0) 6 (40.0) 3 (20.0) 10 (66.7) 12 (80.0) 6 (40.0)
Values are mean ± SD or n (%). There were no statistically significant differences between the groups. a One patient in benzocaine group reported race as both Caucasian and black.
Time 0–time 30
11.1 ( 90.1 to 18.5) 23.5 ( 96.3 to 17.3)
37.0 ( 100 to 1.2) 66.7 ( 100 to 1.2)
Values are median (range). There were no statistically significant differences between the groups. Time 0 = immediately after procedure; time 5 and time 30 = 5 and 30 min after procedure, respectively.
Satisfaction scores.
Values are n (%). There were no statistically significant differences between the groups.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
4
EA Bachman et al.
Discussion
Acknowledgements
This study found no benefit of benzocaine spray for analgesia in a cohort of women undergoing HSG. Although nearly 20-mm difference in pain scores was observed between the groups at the time of the procedure (time 0), the variability in scores was greater than anticipated. This study adds to the existing body of literature examining the optimal analgesic regimen for women undergoing HSG. These findings conflict with previous studies, which demonstrated a benefit to topical analgesia. The first by Kafali et al. (2003) concluded that lidocaine gel provided significant pain relief at the time of tenaculum placement. Subsequently, another report (Robinson et al., 2007) showed that topical lidocaine-prilocaine cream significantly reduced pain at the time of cervical instrumentation, but not during uterine filling and tubal spillage, and another (Lorino et al., 1990) demonstrated that application of 20% benzocaine gel provided significant pain relief. It should be noted that the previous studies were sometimes limited by unclear randomization, blinding and allocation methods. In addition, reliable and valid pain scales were not always used to assess pain as an outcome. The strengths of this study include the randomized, double-blinded, placebo-controlled design. Additionally, it used validated pain scores and also assessed patient satisfaction, which many other studies have not assessed. This study was conducted at the same centre, with similar techniques used by physicians at these sites. It is interesting to note that pain scores widely fluctuated amongst the patients. The majority of patients reported no pain prior to the procedure and then reported a high level of pain during the procedure. These scores quickly decreased to baseline at 5 and 30 min. While an adequate number of patients according to sample size calculation was enrolled, it should be noted that the standard deviations were much wider than anticipated due to both broader range of baseline pain than expected as well as a greater range in change in perceived pain from baseline to time 0. What was most interesting is that, despite many patients reporting pain during the procedure, all of the patients reported satisfaction with the procedure, with the majority of patients in both groups reporting being ‘extremely satisfied’ with the procedure. This suggests that there are other factors involved that influence a patient’s experience during the HSG. Of note, during the HSG in this study centre, one provider performs the HSG and another is always at the bedside speaking to the patient and holding her hand. This emotional support is likely one of the factors contributing to the patients’ satisfaction. In conclusion, benzocaine spray does not decrease pain or expedite resolution of pain during HSG beyond that seen with routine pre-procedure ibuprofen. Additionally, patient satisfaction was not correlated with pain, suggesting this may be influenced by other factors.
This work was supported by the University of Pennsylvania (grant nos. T32-HD040135 and T32-HD007440). The authors would like to thank all participating women, the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology and the Department of Radiology at the Hospital of the University of Pennsylvania. They would also like to thank Dr Kenneth Rockwell Jr of the Investigational Drug Service at the University of Pennsylvania and Elizabeth Steider for their help in the completion of this study.
Trial registration number This trial is registered NCT01925469).
with
ClinicalTrials.gov
(no.
References Ahmad, G., Duffy, J., Watson, A.J., 2007. Pain relief in hysterosalpingography. Cochrane Database Syst. Rev., CD006106. Ayida, G., Kennedy, S., Barlow, D., Chamberlain, P., 1996. A comparison of patient tolerance of hysterosalpingo-contrast sonography (HyCoSy) with Echovist-200 and X-ray hysterosalpingography for outpatient investigation of infertile women. Ultrasound Obstet. Gynecol. 7, 201–204. Barnhart, K., Hummel, A.C., Sammel, M.D., Menon, S., Jain, J., Chakhtoura, N., 2007. Use of ‘2-dose’ regimen of methotrexate to treat ectopic pregnancy. Fertil. Steril. 87, 250–256. Cengiz, M., Kafali, H., Artuc, H., Baysal, Z., 2006. Opioid analgesia for hysterosalpingography: controlled double-blind prospective trial with remifentanil and placebo. Gynecol. Obstet. Invest. 62, 168–172. Costello, M.F., Horrowitz, S., Steigrad, S., Saif, N., Bennett, M., Ekangaki, A., 2002. Transcervical intrauterine topical local anesthetic at hysterosalpingography: a prospective, randomized, double-blind, placebo-controlled trial. Fertil. Steril. 78, 1116–1122. Costello, M.F., Steigrad, S., Collet, A., 2005. A prospective, randomised, single-blinded, controlled trial comparing two topical anaesthetic modalities for the application of a tenaculum to the cervix. J. Obstet. Gynaecol. 25, 781–785. DeLoach, L.J., Higgins, M.S., Caplan, A.B., Stiff, J.L., 1998. The visual analog scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesth. Analg. 86, 102–106. Elson, E.M., Ridley, N.T., 2000. Paracetamol as a prophylactic analgesic for hysterosalpingography: a double blind randomized controlled trial. Clin. Radiol. 55, 675–678. Frishman, G.N., Spencer, P.K., Weitzen, S., Plosker, S., Shafi, F., 2004. The use of intrauterine lidocaine to minimize pain during hysterosalpingography: a randomized trial. Obstet. Gynecol. 103, 1261–1266. Kafali, H., Cengiz, M., Demir, N., 2003. Intrauterine lidocaine gel application for pain relief during and after hysterosalpingography. Int. J. Gynaecol. Obstet. 83, 65–67. Liberty, G., Gal, M., Halevy-Shalem, T., Michaelson-Cohen, R., Galoyan, N., Hyman, J., Eldar-Geva, T., Vatashsky, E., Margalioth, E., 2007. Lidocaine-prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study. Hum. Reprod. 22, 1335–1339. Lorino, C.O., Prough, S.G., Aksel, S., Abuzeid, M., Alexander, S.E., Wiebe, R.H., 1990. Pain relief in hysterosalpingography. A comparison of analgesics. J. Reprod. Med. 35, 533–536. Owens, O.M., Schiff, I., Kaul, A.F., Cramer, D.C., Burt, R.A., 1985. Reduction of pain following hysterosalpingogram by prior analgesic administration. Fertil. Steril. 43, 146–148.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
Pain relief at hysterosalpingogram Peters, A.A., Witte, E.H., Damen, A.C., Holm, J.P., Drogendijk, A.C., vd Velde, E.A., Trimbos, J.B., 1996. Pain relief during and following outpatient curettage and hysterosalpingography: a double blind study to compare the efficacy and safety of tramadol versus naproxen. Cobra Research Group. Eur. J. Obstet. Gynecol. Reprod. Biol. 66, 51–56. Robinson, R.D., Casablanca, Y., Pagano, K.E., Arthur, N.A., Bates, G.W., Propst, A.M., 2007. Intracervical block and pain percep-
5 tion during the performance of a hysterosalpingogram: a randomized controlled trial. Obstet. Gynecol. 109, 89–93. Declaration: The authors report no financial or commercial conflicts of interest. Received 29 October 2013; refereed 5 January 2014; accepted 17 February 2014.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
www.sciencedirect.com www.rbmonline.com
ARTICLE
Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram EA Bachman a, S Senapati
a,*
, MD Sammel b, SK Kalra
a
a University of Pennsylvania, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, 3701 Market Street, Suite 800, Philadelphia, PA 19104, United States b University of Pennsylvania School of Medicine, Department of Biostatistics and Epidemiology, 3451 Walnut Street, Philadelphia, PA 19104, United States
* Corresponding author. E-mail address: [email protected] (S Senapati). Dr. Emelia A Bachman graduated from the Weill Medical College of Cornell University, USA in 2006. She then pursued her residency in obstetrics and gynaecology at the University of Maryland Medical Center (2006–2008) and the Hospital of the University of Pennsylvania (2008–2010). Dr. Bachman completed her fellowship in reproductive endocrinology and infertility at the Hospital of the University of Pennsylvania in 2013. She is a board-certified obstetrician and gynaecologist and is currently a reproductive endocrinologist at Reproductive Associates of Delaware in Newark, Delaware.
Abstract Many women experience pain during hysterosalpingogram (HSG). This prospective, randomized, double-blinded,
placebo-controlled study assessed whether the use of benzocaine spray during HSG is associated with reduced pain as compared with placebo. Thirty women presenting for HSG were enrolled and randomized to either benzocaine or saline spray. Treatment groups were similar in age, race, parity, pre-procedure oral analgesic use and history of dysmenorrhoea and/or chronic pelvic pain. Median change in pain score from baseline to procedure was 50.6 mm ( 7.4 to 98.8 mm) in the benzocaine group and 70.4 mm (19.8 to 100 mm) in the placebo group. There was no difference between groups after adjusting for history of dysmenorrhoea. There was no difference in resolution of pain in benzocaine versus placebo groups at 5 min post procedure – median pain score difference 11.1 ( 90.1 to 18.5) versus 37.0 ( 100 to 1.2) – or at 30 min post procedure. Satisfaction scores did not differ by treatment and did not correlate with pain score during the procedure (rho = 0.005). The use of benzocaine spray does not significantly improve pain relief during HSG nor does it hasten resolution of pain post HSG. Of interest, patient satisfaction was not correlated with pain. RBMOnline ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: analgesia, benzocaine, HSG, hysterosalpingogram, pain relief, randomized controlled trial
http://dx.doi.org/10.1016/j.rbmo.2014.02.012 1472-6483/ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
2
Introduction Hysterosalpingogram (HSG) is an integral part of the evaluation of subfertile women, as it can be used to both evaluate intrauterine pathology and tubal patency. Poor pain control can often limit the quality of the examination. Furthermore, anticipation of pain may preclude patient acceptance of the examination and cause unnecessary anxiety. Up to 72% of women complain of pain during hysterosalpingography (Ayida et al., 1996). There is little consensus regarding the optimal management of pain during HSG. A Cochrane review of the current literature investigating pharmacological interventions for pain relief during HSG found no evidence of benefit when using pain relief medication compared with placebo both during and immediately after the procedure, but did demonstrate that there was a limited benefit 30 min after the procedure (Ahmad et al., 2007). Oral, intrauterine and topical analgesics have been evaluated for pain relief at HSG (Ahmad et al., 2007; Ayida et al., 1996; Cengiz et al., 2006; Costello et al., 2002, 2005; Elson and Ridley, 2000; Frishman et al., 2004; Kafali et al., 2003; Liberty et al., 2007; Lorino et al., 1990; Owens et al., 1985; Peters et al., 1996; Robinson et al., 2007). Application of 20% benzocaine gel to the cervix has been shown to provide significant relief during HSG in one study (Lorino et al., 1990) while another suggested that application of lidocaine to the uterine cervix significantly reduces pain at the time of cervical instrumentation, but not during uterine filling and spillage (Robinson et al., 2007). However, interpretation of the current literature is limited by lack of blinding, placebo control, randomization and unclear allocation. Only two of the eight studies included in the Cochrane review performed a power calculation. In addition, the pain scales used were not always reliable and valid. Also, in cases where the pain scores were significantly different when compared with placebo, patient satisfaction was not always assessed. Given these limitations in the literature, there is currently no consensus on the optimal analgesic regimen during HSG. This work performed a randomized, double-blinded, placebo-controlled investigation to address these limitations. The primary objective was to assess if benzocaine spray was associated with greater pain relief during after HSG compared with placebo. The secondary objective was to assess if the use of benzocaine spray was associated with greater patient satisfaction after HSG.
EA Bachman et al. procedure in this practice, pre-procedure ibuprofen was recommended. Informed consent was obtained on the day of HSG. Patients who consented were randomized to either benzocaine or saline placebo spray. Randomization was performed by the Investigational Drug Service at the Hospital of the University of Pennsylvania via a computer-generated random-number sequence in blocks of four. Drug canisters were blinded to both patient and clinician. All hysterosalpingograms were performed in a single centre by the same group of physicians in a similar fashion. The hysterosalpingogram was performed with the patient in modified dorsal lithotomy position. A sterile speculum was placed by the provider and the cervix cleansed with chlorhexidine solution. Benzocaine or placebo saline was sprayed on the anterior lip of the cervix prior to application of a single-tooth tenaculum. The acorn cannula was inserted into the cervix. Approximately 5–10 ml water-soluble contrast dye was injected under fluoroscopy. Pain scores were obtained using a validated visual analogue scale (DeLoach et al., 1998) pre-procedure, immediately after HSG (designated as time 0) and at 5 and 30 min post procedure. Satisfaction was assessed at 30 min post procedure. Satisfaction was measured using a validated satisfaction survey (Barnhart et al., 2007) on a 5-point scale, 1 representing least satisfied and 5 extremely satisfied. The primary outcome was defined as the difference in pain score from pre-procedure to procedure (time 0). Secondary outcomes included pain resolution (time 0 to time 5, and time 0 to time 30) and patient satisfaction.
Statistical analysis An a priori sample size calculation determined at least 28 patients were needed to detect a clinically significant 13 mm difference in pain score (a = 0.05, power = 0.80) with a standard deviation of 12 mm. Intention-to-treat analysis was performed. t-Test or Fisher’s exact test was used to evaluate differences in risk factors. Differences in the median change in pain scores were assessed using Wilcoxon rank-sum test. Fisher’s exact test was used to assess differences in satisfaction scores by treatment group. Correlation between pain and satisfaction scores was assessed by Spearman’s correlation coefficient. To analyse the change in pain score over time, a random-effects linear regression model was used to account for each individual’s baseline in pain scores. STATA statistical software version 12.0 (StatCorp, College Station, TX, USA) was used for all statistical analyses.
Materials and methods Results This randomized, double-blinded, placebo-controlled trial was conducted from December 2011 to April 2012 at the University of Pennsylvania after approval was obtained from the Institutional Review Board (protocol no. 809399, approved 15 December 2011). All women over the age of 18 who had been referred for hysterosalpingography during this period were deemed eligible. All patients scheduled for HSG at the institution were contacted to enrol in the study. Patients were excluded if they had a positive pregnancy test on the day of HSG or if they reported a hypersensitivity to benzocaine or related analgesic agents. As per routine
Thirty women consented the day of procedure (Figure 1). Only 29 patients received either benzocaine or placebo saline spray due to a single canister malfunction. Fifteen patients were analysed in the placebo group and 15 in the benzocaine group. The baseline characteristics were not statistically different between both groups. Patients were similar in age, race, parity, history of dysmenorrhoea and history of chronic pelvic pain (Table 1). Additionally, there was no difference in the groups with respect to the use of pre-procedure ibuprofen or other oral medication.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
Pain relief at hysterosalpingogram
3 100.0
Assessed for eligibility (n = 47)
90.0
Enrollment
Not meeting inclusion criteria (n = 0) Declined to participate (n = 17)
Pain score (mm)
80.0 Excluded (n = 17)
70.0 60.0 50.0 Benzocaine
40.0
Placebo
30.0 20.0 10.0
Randomized (n = 30)
0.0
Analysis
Follow-up
Allocation
Time (min) Allocated to benzocaine (n = 15) Received allocated intervention (n = 14) Did not receive allocated intervention (n = 1) (due to canister malfunction)
Allocated to placebo (n = 15) Received allocated placebo (n = 15) Did not receive allocated placebo (n = 0)
Lost to follow-up (n = 0) Discontinued intervention (n = 0)
Lost to follow-up (n = 0) Discontinued intervention (n = 0)
Analysed (n = 15) Excluded from analysis (n = 0)
Figure 1
Analysed (n = 15) Excluded from analysis (n = 0)
CONSORT flow diagram.
(One patient in the placebo group and two in the benzocaine group took acetaminophen due to an allergy). When comparing the results of HSG, there were no differences in the proportion of patients with unilateral or bilateral tubal obstruction between the two groups. No patients had uterine anomalies. The median change in pain score from baseline to immediately post procedure was not significantly different
Table 1
Figure 2
Median pain scores. Values are median and range.
between the benzocaine and placebo groups (Figure 2). The differences in pain scores were median (range) 50.6 mm ( 7.4 to 98.8 mm) in the benzocaine group and 70.4 mm (19.8 to 100 mm) in the placebo group. Resolution of pain at 5 min post procedure was not different between the two groups. The pain score difference at this time point was 11.1 ( 90.1 to 18.5) in the benzocaine group and 37.0 ( 100 to 1.2) in the placebo group. At 30 min post procedure, there was no difference in resolution of pain from baseline (Table 2). Even after adjusting for a history of dysmenorrhoea or chronic pelvic pain, these scores were not impacted. When evaluating satisfaction scores, all patients reported being ‘satisfied’, ‘highly satisfied’ or ‘extremely satisfied’ (Table 3). The majority of patients reported being ‘extremely satisfied’ in both groups (71.4% versus 71.4%). Patient satisfaction did not correlate with pain score during the procedure (rho = 0.005). Table 2
Median changes in pain score.
Time interval
Benzocaine (mm)
Placebo (mm)
Baseline–time 0 Time 0–time 5
50.6 ( 7.4 to 98.8)
70.4 (19.8 to 100)
Baseline characteristics.
x Age (years) Racea Caucasian Black Asian Nulligravid Nulliparous History of dysmenorrhoea History of chronic pelvic pain Premedication Bilateral obstruction Unilateral obstruction
Benzocaine (n = 15)
Placebo (n = 15)
34.3 ± 4.8 xxx 8 (53.3) 5 (33.3) 1 (6.7) 7 (46.7) 12 (80.0) 7 (46.7)
33.3 ± 6.5
2 (13.3)
2 (13.3)
Table 3
15 (100) 2 (13.3) 4 (26.7)
13 (86.7) 1 (6.7) 3 (20.0)
Satisfaction score
Benzocaine (n = 14)
Placebo (n = 14)
3 4 5
2 (14.3) 2 (14.3) 10 (71.4)
0 (0) 4 (28.6) 10 (71.4)
6 (40.0) 6 (40.0) 3 (20.0) 10 (66.7) 12 (80.0) 6 (40.0)
Values are mean ± SD or n (%). There were no statistically significant differences between the groups. a One patient in benzocaine group reported race as both Caucasian and black.
Time 0–time 30
11.1 ( 90.1 to 18.5) 23.5 ( 96.3 to 17.3)
37.0 ( 100 to 1.2) 66.7 ( 100 to 1.2)
Values are median (range). There were no statistically significant differences between the groups. Time 0 = immediately after procedure; time 5 and time 30 = 5 and 30 min after procedure, respectively.
Satisfaction scores.
Values are n (%). There were no statistically significant differences between the groups.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
4
EA Bachman et al.
Discussion
Acknowledgements
This study found no benefit of benzocaine spray for analgesia in a cohort of women undergoing HSG. Although nearly 20-mm difference in pain scores was observed between the groups at the time of the procedure (time 0), the variability in scores was greater than anticipated. This study adds to the existing body of literature examining the optimal analgesic regimen for women undergoing HSG. These findings conflict with previous studies, which demonstrated a benefit to topical analgesia. The first by Kafali et al. (2003) concluded that lidocaine gel provided significant pain relief at the time of tenaculum placement. Subsequently, another report (Robinson et al., 2007) showed that topical lidocaine-prilocaine cream significantly reduced pain at the time of cervical instrumentation, but not during uterine filling and tubal spillage, and another (Lorino et al., 1990) demonstrated that application of 20% benzocaine gel provided significant pain relief. It should be noted that the previous studies were sometimes limited by unclear randomization, blinding and allocation methods. In addition, reliable and valid pain scales were not always used to assess pain as an outcome. The strengths of this study include the randomized, double-blinded, placebo-controlled design. Additionally, it used validated pain scores and also assessed patient satisfaction, which many other studies have not assessed. This study was conducted at the same centre, with similar techniques used by physicians at these sites. It is interesting to note that pain scores widely fluctuated amongst the patients. The majority of patients reported no pain prior to the procedure and then reported a high level of pain during the procedure. These scores quickly decreased to baseline at 5 and 30 min. While an adequate number of patients according to sample size calculation was enrolled, it should be noted that the standard deviations were much wider than anticipated due to both broader range of baseline pain than expected as well as a greater range in change in perceived pain from baseline to time 0. What was most interesting is that, despite many patients reporting pain during the procedure, all of the patients reported satisfaction with the procedure, with the majority of patients in both groups reporting being ‘extremely satisfied’ with the procedure. This suggests that there are other factors involved that influence a patient’s experience during the HSG. Of note, during the HSG in this study centre, one provider performs the HSG and another is always at the bedside speaking to the patient and holding her hand. This emotional support is likely one of the factors contributing to the patients’ satisfaction. In conclusion, benzocaine spray does not decrease pain or expedite resolution of pain during HSG beyond that seen with routine pre-procedure ibuprofen. Additionally, patient satisfaction was not correlated with pain, suggesting this may be influenced by other factors.
This work was supported by the University of Pennsylvania (grant nos. T32-HD040135 and T32-HD007440). The authors would like to thank all participating women, the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology and the Department of Radiology at the Hospital of the University of Pennsylvania. They would also like to thank Dr Kenneth Rockwell Jr of the Investigational Drug Service at the University of Pennsylvania and Elizabeth Steider for their help in the completion of this study.
Trial registration number This trial is registered NCT01925469).
with
ClinicalTrials.gov
(no.
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Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
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5 tion during the performance of a hysterosalpingogram: a randomized controlled trial. Obstet. Gynecol. 109, 89–93. Declaration: The authors report no financial or commercial conflicts of interest. Received 29 October 2013; refereed 5 January 2014; accepted 17 February 2014.
Please cite this article in press as: Bachman, EA et al. Randomized controlled trial of benzocaine versus placebo spray for pain relief at hysterosalpingogram. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.012
