- Email: [email protected]
Ibuprofen prophylaxis for levonorgestrel-releasing intrauterine system insertion: a randomized controlled trial
Contraception 85 (2012) 558 – 562
Original research article
Ibuprofen prophylaxis for levonorgestrel-releasing intrauterine system insertion: a randomized controlled trial☆ Julie Chor a,⁎, Julia Bregand-White b , Alex Golobof b , Bryna Harwood b , Allison Cowett b a Department of Obstetrics and Gynecology, John H. Stroger Jr. Hospital of Cook County, Chicago, IL 60612, USA Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA Received 29 September 2011; revised 20 October 2011; accepted 21 October 2011
b
Abstract Background: Despite the high efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) in preventing pregnancy, uptake of the intrauterine devices remains low in the United States. Decreasing pain at the time of intrauterine device insertion may be one way to increase interest in this method of contraception. Study Design: We conducted a double-blind, placebo-controlled trial, randomizing women to 800 mg ibuprofen or placebo 45 min prior to LNG-IUS insertion to determine effect of ibuprofen on the pain of LNG-IUS insertion. Results: Eighty-one women completed the study: 44 received ibuprofen, and 37 received placebo. Women in the ibuprofen and placebo groups had similar mean scores for anticipated pain (4.07 and 3.91, respectively; p=.79), pain with tenaculum placement (3.86 and 3.81, respectively; p=.90) and pain with insertion (3.69 and 3.34, respectively; p=.91). Conclusion: Administration of ibuprofen prophylaxis for LNG-IUS insertion does not decrease pain at the time of insertion. © 2012 Elsevier Inc. All rights reserved. Keywords: Intrauterine contraception; Analgesia; Pain management
1. Introduction Despite a 12-month efficacy rate of 99.2%–99.8% for the levonorgestrel-releasing and the copper intrauterine devices (IUDs), the most recent data find that only 5.5% of women in the United States 15–44 years old using contraception currently use an IUD [1,2]. The low rate of IUD use in the United States may be related in part to fear of pain at the time of device insertion. Therefore, decreasing pain at the time of IUD insertion may play a crucial role in increasing IUD uptake. Previous studies looking into methods of decreasing IUD insertion pain have included cervical priming, local anesthesia and systemic analgesia. Several studies have examined the effect of premedication with nonsteroidal anti-inflammatory medications on IUD insertion pain. One study from 1974 found that women who received naproxen prior to Dalkon Shield IUD ☆
There was no funding provided for this project. ⁎ Corresponding author. Tel.: +1 312 864 5240; fax: +1 312 864 9782. E-mail address: [email protected] (J. Chor).
0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.10.015
insertion had less pain compared to women who received placebo [3]. Two studies that randomized women to either placebo or ibuprofen before insertion of a copper IUD found no difference in pain at IUD insertion between the two groups [4,5]. While several studies have looked at strategies to decrease pain at the time of copper IUD insertion, the current literature does not include any randomized trials comparing the effect of prophylactic use of nonsteroidals versus placebo specifically on pain at the time of levonorgestrel-releasing intrauterine system (LNG-IUS) insertion [6]. While the diameter of the copper IUD inserter is 4.0 mm, the inserter of the LNG-IUS is 4.65– 4.85 mm, which may confer slightly more discomfort with insertion [7,8]. Additionally, neither of the previous studies evaluating the effect of ibuprofen on the pain at the time of IUD insertion using contemporary IUDs was conducted using a US study population [4,5]. Therefore, the primary objective of this study is to determine whether ibuprofen administration 45 min before insertion decreases the pain at the time of the LNG-IUS insertion.
J. Chor et al. / Contraception 85 (2012) 558–562
2. Methods We conducted a randomized trial at the University of Illinois Medical Center between April 2007 and January 2010. The Institutional Review Board at the University of Illinois at Chicago approved the study protocol. Women were eligible for participation in this study if they (a) were 18 years and older, (b) were desiring LNG-IUS for contraception, (c) were without contraindications to using LNG-IUS, (d) were without medical contraindications to nonsteroidal anti-inflammatory drugs (NSAIDs), (e) were able to provide a phone number for follow-up questions and (f) had not taken pain medications on the day of enrollment. We recruited participants in the university's women's outpatient clinic where providers participating in the study included OBGYN residents, attending physicians and nurse midwives. We concluded the study upon completion of participant recruitment. Members of the research team approached women coming to the clinic for LNG-IUS insertion at the beginning of their clinic appointment to inform them about the study. After a description of the study, research team members screened women for eligibility and obtained informed consent. Participants received either placebo containing lactose or ibuprofen 800 mg approximately 45 min prior to IUD insertion. Both placebo and ibuprofen were identical in appearance. During this wait time, participants completed a questionnaire detailing their demographic, contraceptive and gynecologic history. A colleague not involved in participant recruitment or enrollment created a computer-generated randomization assignment list and packaged study medications and data collection sheets in serially numbered envelopes. Study team members took envelopes in order and assigned identification numbers to each participant after enrollment in the study, ensuring that participants, providers and study recruiters were blinded to medication administered. After signing consent forms, taking the study medication and completing the initial questionnaire, participants underwent LNG-IUS insertion in the standard manner as performed by their provider. Participants did not receive local anesthetic prior to insertion. Providers performed preprocedure counseling and consent forms according to clinic protocols. Participants rated the level of pain that they anticipated experiencing prior to insertion, the pain at the time of tenaculum placement and pain at the time of IUD insertion by marking a 10-cm visual analog scale (VAS, endpoints 0=no pain and 10=unbearable). Participants also compared the pain at IUD insertion to the pain at the time of menses. Providers completed a short questionnaire on their experience with ease of insertion and additional need for dilation. We compared the demographic, baseline and mean pain data for both groups using appropriate statistical tests (χ 2 for categorical data and t test or the Wilcoxon signed-rank test for continuous data) using a two-tailed p value of .05.
559
We conducted all data management and analysis using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). We calculated the sample size needed a priori to detect a difference of 1.5 cm in the VAS assessment of pain at the time of IUD insertion with 80% power and an alpha of 0.05, resulting in a sample size of 37 participants needed in each group. We chose a standard deviation of 23 mm based on previous work assessing pain with cervical and uterine manipulation [9]. In order to reach the goal of 37 participants in each group, study team members recruited additional participants as several participants were excluded after being randomized.
3. Results A total of 87 women enrolled in the study: 40 participants received placebo, and 47 received ibuprofen. Six participants (three in each group) chose not to have their IUDs placed after the study medication was ingested and were excluded from this analysis. The data presented represent the 81 participants who received IUDs: 37 in the placebo group and 44 in the ibuprofen group. The demographic characteristics of the two groups were comparable regarding gravidity, parity, race, marital status and education; however, the placebo and ibuprofen groups differed significantly with regards to mean age (27.9 vs. 24.7 years, respectively; p=.0121) (Table 1). As members of the study team were only able to recruit study participants on days that team members were available, complete data on the number of eligible participants are not available (Fig. 1). We did not collect data on participants who declined to participate or who were ineligible to participate in this study. The mean time from medication administration to IUD insertion did not differ significantly between the two groups Table 1 Demographic characteristics of study participants
c
Age, years Gravidity a Nulliparity Multiparity Spontaneous vaginal deliverya Race/ethnicity b African–American Latina White Asian Other Educationb ≤High school NHigh school Time interval (min) c
Placebo (n=37)
Ibuprofen (n=44)
p
27.89 (6.5) 2.62 (1.5) 0 (0%) 37 (100%) 1.16 (1.0)
24.66 (5.4) 2.38 (1.5) 3 (6.8%) 41 (93.2%) 1.00 (1.1)
.01
22 (59.5%) 8 (21.6%) 4 (10.8%) 0 (0%) 3 (8.1%)
24 (54.6%) 14 (31.8%) 5 (11.4%) 1 (2.3%) 0 (0%)
20 (54.1%) 17 (46.0%) 47.73 (18.3)
25 (56.8%) 19 (43.2%) 43.34 (13.7)
.51 .26
.06
Values are mean (standard deviation) or n (%). a Independent t test. b χ 2 test. c Wilcoxon test.
.26
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J. Chor et al. / Contraception 85 (2012) 558–562
87 women enrolled
40 placebo
47 ibuprofen
3 IUDs not placed
3 IUDs not placed
37 placebo
44 ibuprofen
Fig. 1. Participant flow.
(47.73 min in the placebo group compared to 43.34 min in the ibuprofen group; p=.26). Women in the placebo and ibuprofen groups did not differ significantly regarding the mean level of pain that they anticipated prior to IUD insertion (3.91 vs. 4.07, respectively; p=.79) (Table 2). The mean pain scores at the time of IUD insertion did not differ significantly between the placebo and ibuprofen groups (3.34 vs. 3.69, respectively; p=.91). Similarly, women who received placebo versus ibuprofen did not differ significantly in mean pain at the time of tenaculum placement (3.81 vs. 3.86, respectively; p=.90). Both groups experienced more pain at the time of tenaculum placement compared to IUD insertion. Both groups experienced less pain at the time of IUD insertion compared to the pain that they anticipated experiencing, though the difference between actual and anticipated pain did not differ between the placebo and ibuprofen groups (−.60 vs. −.43, respectively; p=.85). Furthermore, the two groups did not differ regarding how
Placebo (n=37)
Ibuprofen (n=44)
p
3.91 (2.2) d 3.81 (3.0) e 3.34 (2.7) −.60 (3.6) d 3.31 (2.9) e
4.07 (2.9) f 3.86 (2.9) f 3.69 (3.4) −.43 (4.2) f 3.07 (3.0) g
.79 .90 .91 .85 .72 .39
16 (44.4%) e 8 (25.0%) e 11 (30.6%) e
Values are mean (standard deviation) or n (%). a Independent t test. b χ 2 test. c Wilcoxon test. d Values based on n=35. e Values based on n=36. f Values based on n=42. g Values based on n=43.
4. Discussion We compared the pain at the time of LNG-IUS insertion in women who received ibuprofen 800 mg versus placebo
Table 2 Patient pain scores using 10-cm visual analog scale
Anticipated pain a Pain at tenaculum c Pain at IUD insertion c Pain at IUD−pain anticipated a Pain at menses a Pain at IUD insertion compared to menses b Less pain Same pain More pain
the pain of IUD insertion compared to pain at the time of menses (p=.39). There was no difference in regards to history of pain syndromes including dysmenorrhea, dyspareunia, chronic pelvic pain, fibroids or endometriosis (data not included in tables). With regards to provider data, there were no significant differences in the distribution of practitioner type, resistance met at time of insertion or whether additional dilation was required between both groups (Table 3). In both the placebo group and the ibuprofen group, resident physicians placed most of the IUDs (80% and 84.1%, respectively), most practitioners encountered either no or mild resistance at the time of IUD insertion (97.1% and 79.5%, respectively), and most providers did not require additional dilation prior to IUD insertion (97.1% and 95.5%, respectively). No adverse events were encountered during the study period.
15 (34.1%) 9 (20.5%) 20 (45.5%)
Table 3 Provider IUD insertion data
Practitioner type Certified nurse midwives OBGYN attending OBGYN resident Resistance at IUD insertion No resistance Mild resistance Moderate resistance Severe resistance Additional dilation needed No Yes Values are n (%). χ 2 test. a Values based on n=34. b Values based on n=35.
Placebo (n=37)
Ibuprofen (n=44)
2 (5.7%) b 5 (14.3%) b 28 (80%) b
1 (2.3%) 6 (13.6%) 37 (84.1%)
17 (50.0%) a 16 (47.1%) a 1 (2.9%) a 0 (0%) a
19 (43.2%) 16 (36.4%) 8 (18.2%) 1 (2.3%)
33 (97.1%) a 1 (2.9%) a
42 (95.5%) 2 (4.6%)
p .72
.14
.71
J. Chor et al. / Contraception 85 (2012) 558–562
approximately 45 min prior to insertion and failed to find a difference in insertion pain between the two treatment groups. This finding is disappointing as ibuprofen is a widely available, well-tolerated and inexpensive method of analgesia used successfully in many other clinical settings. While we randomly assigned our study participants to receive either ibuprofen or placebo, we did not stratify randomization by gravidity, nor did we restrict our participants based on gravidity. Therefore, we only had three nulliparas in the ibuprofen group and no nulliparas in the placebo group and are unable to perform subgroup analyses based on gravidity. Although it is reasonable to expect that nulliparas might have increased pain at the time of IUD insertion and, therefore, benefit more from an intervention to decrease the pain at the time of insertion than parous women, our trial is not able to address this issue. Additionally, as we conducted this study at a teaching institution with resident physicians, the inclusion of possibly less experienced providers may have affected the participants' experiences with IUD insertions. Furthermore, we premedicated participants approximately 45 min prior to IUD insertion in order to use an interval that would not greatly hinder clinic flow. As the mean interval from premedication with ibuprofen to insertion was 43 min in the ibuprofen group, it is possible that the medication was not given long enough prior to IUD insertion to have adequate effect as peak serum levels are attained at 1–2 h after administration [10]. This study has several strengths. As previously stated, this is the first trial to specifically evaluate the effect of ibuprofen on pain at the time of LNG-IUS insertion and using a US population. Whereas previous studies used 400 or 600 mg of ibuprofen, we used a higher dose of 800 mg to optimize the potential analgesic effect of ibuprofen. The use of a prospective, double-blinded, randomized control trial to compare the two treatment arms allowed us to minimize potential biases that an unblinded or observational trial would have introduced. Additionally, because we excluded women who had taken other pain medications on the day of insertion, we were able to truly assess the effect of ibuprofen on the pain at the time of IUD insertion. Finally, we were adequately powered to detect a clinically significant difference in pain scores. Our results comparing the effect of ibuprofen versus placebo on the pain at the time of LNG-IUS insertion are consistent with two trials that failed to find a difference in the pain at the time of copper IUD insertion between women receiving ibuprofen versus placebo [4,5]. Other studies looking at alternative methods of analgesia and cervical priming prior to IUD insertion have found inconsistent results. Older observational studies exploring the use of local anesthesia prior to IUD insertion have described topical uterine anesthesia using lavage of the uterine cavity with 1% lidocaine, jet injection paracervical block and paracervical block using a dental aspiration syringe [11–13]. These studies showed varying degrees of improvement in pain at
561
the time of IUD insertion. In 1996, Oloto et al. [14] conducted a randomized control trial and found a significant decrease in pain at IUD insertion with application of 2% lignocaine gel in the cervical canal. Two recent studies looking into the use of cervical preparation with misoprostol found no difference in insertion pain with either sublingual or vaginal misoprostol [15,16]. Saav et al. [15] randomized 80 women to either 400 mcg of sublingual misoprostol and 100 mg diclofenac or 100 mg diclofenac alone 1 h pre-IUD insertion. This study found that while the misoprostol group had subjectively easier insertions as measured by the investigator, women's pain at insertion did not differ [15]. Dijkuizen et al. [16] randomized 270 women to receive either 400 mcg of vaginal misoprostol or placebo 3 h prior to insertion and found no benefit to using misoprostol and more side effects in the misoprostol group. In trying to increase women's acceptance of long-acting reversible contraception (LARC) in general and IUDs in particular, LARC providers must continue to strive to decrease barriers to uptake of these methods, including pain at the time of insertion. We had hoped to find that prophylactic ibuprofen prior to LNG-IUS insertion would improve the pain at the time of IUS insertion. We found that the pain of IUS insertion was similar between women who received either ibuprofen or placebo and that insertion pain was similar to the pain that women had anticipated prior to insertion. We also found that tenaculum placement was actually more painful than IUS insertion in both placebo and ibuprofen groups. Future research looking into ways to decrease the pain of tenaculum placement is therefore warranted. Interestingly, the mean insertion pain levels in both of our study groups (3.3 with placebo and 3.9 with ibuprofen) were higher than the mean pain level reported by Hubacher et al. [5] who assessed pain at the time of IUD insertion among a population of Chilean women (2 for women who received placebo and 1.8 for women who received ibuprofen prior to copper IUD insertion). These differences may reflect cultural differences in anticipation and perception of pain from IUD insertion and possible differences in how women are counseled about what to expect at the time of IUD insertion. Perhaps, further inquiry into these differences would provide alternative ways to improve women's experiences with IUD insertion in the United States and, in turn, help to increase interest in this highly effective method. Acknowledgment The authors would like to thank the following people for assistance with this project: Jennifer Hardman, Mitzi Wasik, Sana Hussain, and Omolade Oduala. References [1] Trussel J. Contraceptive failure in the United States. Contraception 2011;83:397–404.
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[2] Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. Vital Health Stat 2010;23(29):1–44. [3] Massey SE, Varady JC, Henzl MR. Pain relief with naproxen following insertion of an intrauterine device. J Reprod Med 1974;13:226–31. [4] Jensen HH, Blaabjerg J, Lyndrup J. Prophylactic use of prostaglandin synthetase inhibitors in connection with IUD insertion. Ugeskr Laeger 1998;160:6958–61. [5] Hubacher D, Reyes V, Lillo S, Zepeda A, Chen P, Croxatto H. Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. Am J Obstet Gynecol 2006;195:1272–7. [6] Allen RH, Bartz D, Grimes DA, Hubacher D, O'Brien P. Interventions for pain with intrauterine device insertion. Cochrane Database Syst Rev 2009;8:CD007373. [7] Duramed Pharmaceuticals communication. [8] Bayer Healthcare Pharmaceuticals communication. [9] Edelman A, Nichols MD, Jensen J. Comparison of pain and time of procedures with two first-trimester abortion techniques performed by residents and faculty. Am J Obstet Gynecol 2001;184:1564–7.
[10] Pharmacia Corporation. Motrin® ibuprofen tablets, USP. [11] Hasson H. Topical anesthesia: a preliminary report. Int J Gynaecol Obstet 1977;15:238–40. [12] Kurz KH, Meier-Oehlke P. Jet-injection — local anesthesia for fitting and removal of IUDs. Contracept Deliv Syst 1983;4:27–32. [13] Thiery M. Pain relief at insertion and removal of an IUD: a simplified technique for paracervical block. Adv Contracept 1985;1: 167–70. [14] Oloto EJ, Bromham DR, Murty JA. Pain and discomfort perception at IUD insertion — effect of short-duration, low volume, intracervical application of two per cent lignocaine gel (Instillagel) — a preliminary study. Br J Fam Plann 1996;22:177–80. [15] Sääv I, Aronsson A, Marions L, Stephansson O, Gemzell-Danielsson K. Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: a randomized controlled trial. Hum Reprod 2007;22:2647–52. [16] Dijkhuizen K, Dekkers OM, Holleboom CA, et al. Vaginal misoprostol prior to insertion of an intrauterine device: an RCT. Hum Reprod 2011;26:323–9.
Original research article
Ibuprofen prophylaxis for levonorgestrel-releasing intrauterine system insertion: a randomized controlled trial☆ Julie Chor a,⁎, Julia Bregand-White b , Alex Golobof b , Bryna Harwood b , Allison Cowett b a Department of Obstetrics and Gynecology, John H. Stroger Jr. Hospital of Cook County, Chicago, IL 60612, USA Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA Received 29 September 2011; revised 20 October 2011; accepted 21 October 2011
b
Abstract Background: Despite the high efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) in preventing pregnancy, uptake of the intrauterine devices remains low in the United States. Decreasing pain at the time of intrauterine device insertion may be one way to increase interest in this method of contraception. Study Design: We conducted a double-blind, placebo-controlled trial, randomizing women to 800 mg ibuprofen or placebo 45 min prior to LNG-IUS insertion to determine effect of ibuprofen on the pain of LNG-IUS insertion. Results: Eighty-one women completed the study: 44 received ibuprofen, and 37 received placebo. Women in the ibuprofen and placebo groups had similar mean scores for anticipated pain (4.07 and 3.91, respectively; p=.79), pain with tenaculum placement (3.86 and 3.81, respectively; p=.90) and pain with insertion (3.69 and 3.34, respectively; p=.91). Conclusion: Administration of ibuprofen prophylaxis for LNG-IUS insertion does not decrease pain at the time of insertion. © 2012 Elsevier Inc. All rights reserved. Keywords: Intrauterine contraception; Analgesia; Pain management
1. Introduction Despite a 12-month efficacy rate of 99.2%–99.8% for the levonorgestrel-releasing and the copper intrauterine devices (IUDs), the most recent data find that only 5.5% of women in the United States 15–44 years old using contraception currently use an IUD [1,2]. The low rate of IUD use in the United States may be related in part to fear of pain at the time of device insertion. Therefore, decreasing pain at the time of IUD insertion may play a crucial role in increasing IUD uptake. Previous studies looking into methods of decreasing IUD insertion pain have included cervical priming, local anesthesia and systemic analgesia. Several studies have examined the effect of premedication with nonsteroidal anti-inflammatory medications on IUD insertion pain. One study from 1974 found that women who received naproxen prior to Dalkon Shield IUD ☆
There was no funding provided for this project. ⁎ Corresponding author. Tel.: +1 312 864 5240; fax: +1 312 864 9782. E-mail address: [email protected] (J. Chor).
0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.10.015
insertion had less pain compared to women who received placebo [3]. Two studies that randomized women to either placebo or ibuprofen before insertion of a copper IUD found no difference in pain at IUD insertion between the two groups [4,5]. While several studies have looked at strategies to decrease pain at the time of copper IUD insertion, the current literature does not include any randomized trials comparing the effect of prophylactic use of nonsteroidals versus placebo specifically on pain at the time of levonorgestrel-releasing intrauterine system (LNG-IUS) insertion [6]. While the diameter of the copper IUD inserter is 4.0 mm, the inserter of the LNG-IUS is 4.65– 4.85 mm, which may confer slightly more discomfort with insertion [7,8]. Additionally, neither of the previous studies evaluating the effect of ibuprofen on the pain at the time of IUD insertion using contemporary IUDs was conducted using a US study population [4,5]. Therefore, the primary objective of this study is to determine whether ibuprofen administration 45 min before insertion decreases the pain at the time of the LNG-IUS insertion.
J. Chor et al. / Contraception 85 (2012) 558–562
2. Methods We conducted a randomized trial at the University of Illinois Medical Center between April 2007 and January 2010. The Institutional Review Board at the University of Illinois at Chicago approved the study protocol. Women were eligible for participation in this study if they (a) were 18 years and older, (b) were desiring LNG-IUS for contraception, (c) were without contraindications to using LNG-IUS, (d) were without medical contraindications to nonsteroidal anti-inflammatory drugs (NSAIDs), (e) were able to provide a phone number for follow-up questions and (f) had not taken pain medications on the day of enrollment. We recruited participants in the university's women's outpatient clinic where providers participating in the study included OBGYN residents, attending physicians and nurse midwives. We concluded the study upon completion of participant recruitment. Members of the research team approached women coming to the clinic for LNG-IUS insertion at the beginning of their clinic appointment to inform them about the study. After a description of the study, research team members screened women for eligibility and obtained informed consent. Participants received either placebo containing lactose or ibuprofen 800 mg approximately 45 min prior to IUD insertion. Both placebo and ibuprofen were identical in appearance. During this wait time, participants completed a questionnaire detailing their demographic, contraceptive and gynecologic history. A colleague not involved in participant recruitment or enrollment created a computer-generated randomization assignment list and packaged study medications and data collection sheets in serially numbered envelopes. Study team members took envelopes in order and assigned identification numbers to each participant after enrollment in the study, ensuring that participants, providers and study recruiters were blinded to medication administered. After signing consent forms, taking the study medication and completing the initial questionnaire, participants underwent LNG-IUS insertion in the standard manner as performed by their provider. Participants did not receive local anesthetic prior to insertion. Providers performed preprocedure counseling and consent forms according to clinic protocols. Participants rated the level of pain that they anticipated experiencing prior to insertion, the pain at the time of tenaculum placement and pain at the time of IUD insertion by marking a 10-cm visual analog scale (VAS, endpoints 0=no pain and 10=unbearable). Participants also compared the pain at IUD insertion to the pain at the time of menses. Providers completed a short questionnaire on their experience with ease of insertion and additional need for dilation. We compared the demographic, baseline and mean pain data for both groups using appropriate statistical tests (χ 2 for categorical data and t test or the Wilcoxon signed-rank test for continuous data) using a two-tailed p value of .05.
559
We conducted all data management and analysis using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). We calculated the sample size needed a priori to detect a difference of 1.5 cm in the VAS assessment of pain at the time of IUD insertion with 80% power and an alpha of 0.05, resulting in a sample size of 37 participants needed in each group. We chose a standard deviation of 23 mm based on previous work assessing pain with cervical and uterine manipulation [9]. In order to reach the goal of 37 participants in each group, study team members recruited additional participants as several participants were excluded after being randomized.
3. Results A total of 87 women enrolled in the study: 40 participants received placebo, and 47 received ibuprofen. Six participants (three in each group) chose not to have their IUDs placed after the study medication was ingested and were excluded from this analysis. The data presented represent the 81 participants who received IUDs: 37 in the placebo group and 44 in the ibuprofen group. The demographic characteristics of the two groups were comparable regarding gravidity, parity, race, marital status and education; however, the placebo and ibuprofen groups differed significantly with regards to mean age (27.9 vs. 24.7 years, respectively; p=.0121) (Table 1). As members of the study team were only able to recruit study participants on days that team members were available, complete data on the number of eligible participants are not available (Fig. 1). We did not collect data on participants who declined to participate or who were ineligible to participate in this study. The mean time from medication administration to IUD insertion did not differ significantly between the two groups Table 1 Demographic characteristics of study participants
c
Age, years Gravidity a Nulliparity Multiparity Spontaneous vaginal deliverya Race/ethnicity b African–American Latina White Asian Other Educationb ≤High school NHigh school Time interval (min) c
Placebo (n=37)
Ibuprofen (n=44)
p
27.89 (6.5) 2.62 (1.5) 0 (0%) 37 (100%) 1.16 (1.0)
24.66 (5.4) 2.38 (1.5) 3 (6.8%) 41 (93.2%) 1.00 (1.1)
.01
22 (59.5%) 8 (21.6%) 4 (10.8%) 0 (0%) 3 (8.1%)
24 (54.6%) 14 (31.8%) 5 (11.4%) 1 (2.3%) 0 (0%)
20 (54.1%) 17 (46.0%) 47.73 (18.3)
25 (56.8%) 19 (43.2%) 43.34 (13.7)
.51 .26
.06
Values are mean (standard deviation) or n (%). a Independent t test. b χ 2 test. c Wilcoxon test.
.26
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J. Chor et al. / Contraception 85 (2012) 558–562
87 women enrolled
40 placebo
47 ibuprofen
3 IUDs not placed
3 IUDs not placed
37 placebo
44 ibuprofen
Fig. 1. Participant flow.
(47.73 min in the placebo group compared to 43.34 min in the ibuprofen group; p=.26). Women in the placebo and ibuprofen groups did not differ significantly regarding the mean level of pain that they anticipated prior to IUD insertion (3.91 vs. 4.07, respectively; p=.79) (Table 2). The mean pain scores at the time of IUD insertion did not differ significantly between the placebo and ibuprofen groups (3.34 vs. 3.69, respectively; p=.91). Similarly, women who received placebo versus ibuprofen did not differ significantly in mean pain at the time of tenaculum placement (3.81 vs. 3.86, respectively; p=.90). Both groups experienced more pain at the time of tenaculum placement compared to IUD insertion. Both groups experienced less pain at the time of IUD insertion compared to the pain that they anticipated experiencing, though the difference between actual and anticipated pain did not differ between the placebo and ibuprofen groups (−.60 vs. −.43, respectively; p=.85). Furthermore, the two groups did not differ regarding how
Placebo (n=37)
Ibuprofen (n=44)
p
3.91 (2.2) d 3.81 (3.0) e 3.34 (2.7) −.60 (3.6) d 3.31 (2.9) e
4.07 (2.9) f 3.86 (2.9) f 3.69 (3.4) −.43 (4.2) f 3.07 (3.0) g
.79 .90 .91 .85 .72 .39
16 (44.4%) e 8 (25.0%) e 11 (30.6%) e
Values are mean (standard deviation) or n (%). a Independent t test. b χ 2 test. c Wilcoxon test. d Values based on n=35. e Values based on n=36. f Values based on n=42. g Values based on n=43.
4. Discussion We compared the pain at the time of LNG-IUS insertion in women who received ibuprofen 800 mg versus placebo
Table 2 Patient pain scores using 10-cm visual analog scale
Anticipated pain a Pain at tenaculum c Pain at IUD insertion c Pain at IUD−pain anticipated a Pain at menses a Pain at IUD insertion compared to menses b Less pain Same pain More pain
the pain of IUD insertion compared to pain at the time of menses (p=.39). There was no difference in regards to history of pain syndromes including dysmenorrhea, dyspareunia, chronic pelvic pain, fibroids or endometriosis (data not included in tables). With regards to provider data, there were no significant differences in the distribution of practitioner type, resistance met at time of insertion or whether additional dilation was required between both groups (Table 3). In both the placebo group and the ibuprofen group, resident physicians placed most of the IUDs (80% and 84.1%, respectively), most practitioners encountered either no or mild resistance at the time of IUD insertion (97.1% and 79.5%, respectively), and most providers did not require additional dilation prior to IUD insertion (97.1% and 95.5%, respectively). No adverse events were encountered during the study period.
15 (34.1%) 9 (20.5%) 20 (45.5%)
Table 3 Provider IUD insertion data
Practitioner type Certified nurse midwives OBGYN attending OBGYN resident Resistance at IUD insertion No resistance Mild resistance Moderate resistance Severe resistance Additional dilation needed No Yes Values are n (%). χ 2 test. a Values based on n=34. b Values based on n=35.
Placebo (n=37)
Ibuprofen (n=44)
2 (5.7%) b 5 (14.3%) b 28 (80%) b
1 (2.3%) 6 (13.6%) 37 (84.1%)
17 (50.0%) a 16 (47.1%) a 1 (2.9%) a 0 (0%) a
19 (43.2%) 16 (36.4%) 8 (18.2%) 1 (2.3%)
33 (97.1%) a 1 (2.9%) a
42 (95.5%) 2 (4.6%)
p .72
.14
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approximately 45 min prior to insertion and failed to find a difference in insertion pain between the two treatment groups. This finding is disappointing as ibuprofen is a widely available, well-tolerated and inexpensive method of analgesia used successfully in many other clinical settings. While we randomly assigned our study participants to receive either ibuprofen or placebo, we did not stratify randomization by gravidity, nor did we restrict our participants based on gravidity. Therefore, we only had three nulliparas in the ibuprofen group and no nulliparas in the placebo group and are unable to perform subgroup analyses based on gravidity. Although it is reasonable to expect that nulliparas might have increased pain at the time of IUD insertion and, therefore, benefit more from an intervention to decrease the pain at the time of insertion than parous women, our trial is not able to address this issue. Additionally, as we conducted this study at a teaching institution with resident physicians, the inclusion of possibly less experienced providers may have affected the participants' experiences with IUD insertions. Furthermore, we premedicated participants approximately 45 min prior to IUD insertion in order to use an interval that would not greatly hinder clinic flow. As the mean interval from premedication with ibuprofen to insertion was 43 min in the ibuprofen group, it is possible that the medication was not given long enough prior to IUD insertion to have adequate effect as peak serum levels are attained at 1–2 h after administration [10]. This study has several strengths. As previously stated, this is the first trial to specifically evaluate the effect of ibuprofen on pain at the time of LNG-IUS insertion and using a US population. Whereas previous studies used 400 or 600 mg of ibuprofen, we used a higher dose of 800 mg to optimize the potential analgesic effect of ibuprofen. The use of a prospective, double-blinded, randomized control trial to compare the two treatment arms allowed us to minimize potential biases that an unblinded or observational trial would have introduced. Additionally, because we excluded women who had taken other pain medications on the day of insertion, we were able to truly assess the effect of ibuprofen on the pain at the time of IUD insertion. Finally, we were adequately powered to detect a clinically significant difference in pain scores. Our results comparing the effect of ibuprofen versus placebo on the pain at the time of LNG-IUS insertion are consistent with two trials that failed to find a difference in the pain at the time of copper IUD insertion between women receiving ibuprofen versus placebo [4,5]. Other studies looking at alternative methods of analgesia and cervical priming prior to IUD insertion have found inconsistent results. Older observational studies exploring the use of local anesthesia prior to IUD insertion have described topical uterine anesthesia using lavage of the uterine cavity with 1% lidocaine, jet injection paracervical block and paracervical block using a dental aspiration syringe [11–13]. These studies showed varying degrees of improvement in pain at
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the time of IUD insertion. In 1996, Oloto et al. [14] conducted a randomized control trial and found a significant decrease in pain at IUD insertion with application of 2% lignocaine gel in the cervical canal. Two recent studies looking into the use of cervical preparation with misoprostol found no difference in insertion pain with either sublingual or vaginal misoprostol [15,16]. Saav et al. [15] randomized 80 women to either 400 mcg of sublingual misoprostol and 100 mg diclofenac or 100 mg diclofenac alone 1 h pre-IUD insertion. This study found that while the misoprostol group had subjectively easier insertions as measured by the investigator, women's pain at insertion did not differ [15]. Dijkuizen et al. [16] randomized 270 women to receive either 400 mcg of vaginal misoprostol or placebo 3 h prior to insertion and found no benefit to using misoprostol and more side effects in the misoprostol group. In trying to increase women's acceptance of long-acting reversible contraception (LARC) in general and IUDs in particular, LARC providers must continue to strive to decrease barriers to uptake of these methods, including pain at the time of insertion. We had hoped to find that prophylactic ibuprofen prior to LNG-IUS insertion would improve the pain at the time of IUS insertion. We found that the pain of IUS insertion was similar between women who received either ibuprofen or placebo and that insertion pain was similar to the pain that women had anticipated prior to insertion. We also found that tenaculum placement was actually more painful than IUS insertion in both placebo and ibuprofen groups. Future research looking into ways to decrease the pain of tenaculum placement is therefore warranted. Interestingly, the mean insertion pain levels in both of our study groups (3.3 with placebo and 3.9 with ibuprofen) were higher than the mean pain level reported by Hubacher et al. [5] who assessed pain at the time of IUD insertion among a population of Chilean women (2 for women who received placebo and 1.8 for women who received ibuprofen prior to copper IUD insertion). These differences may reflect cultural differences in anticipation and perception of pain from IUD insertion and possible differences in how women are counseled about what to expect at the time of IUD insertion. Perhaps, further inquiry into these differences would provide alternative ways to improve women's experiences with IUD insertion in the United States and, in turn, help to increase interest in this highly effective method. Acknowledgment The authors would like to thank the following people for assistance with this project: Jennifer Hardman, Mitzi Wasik, Sana Hussain, and Omolade Oduala. References [1] Trussel J. Contraceptive failure in the United States. Contraception 2011;83:397–404.
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[2] Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. Vital Health Stat 2010;23(29):1–44. [3] Massey SE, Varady JC, Henzl MR. Pain relief with naproxen following insertion of an intrauterine device. J Reprod Med 1974;13:226–31. [4] Jensen HH, Blaabjerg J, Lyndrup J. Prophylactic use of prostaglandin synthetase inhibitors in connection with IUD insertion. Ugeskr Laeger 1998;160:6958–61. [5] Hubacher D, Reyes V, Lillo S, Zepeda A, Chen P, Croxatto H. Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. Am J Obstet Gynecol 2006;195:1272–7. [6] Allen RH, Bartz D, Grimes DA, Hubacher D, O'Brien P. Interventions for pain with intrauterine device insertion. Cochrane Database Syst Rev 2009;8:CD007373. [7] Duramed Pharmaceuticals communication. [8] Bayer Healthcare Pharmaceuticals communication. [9] Edelman A, Nichols MD, Jensen J. Comparison of pain and time of procedures with two first-trimester abortion techniques performed by residents and faculty. Am J Obstet Gynecol 2001;184:1564–7.
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