Effective Pharmacologic Pain Management Interventions for Intrauterine Device Insertion: A Systematic Review and Network Meta-Analysis

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Trefsgar, Katrina Botto, Afreen Hussaini, Bansri Patel, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6590141/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background To identify the most effective pain management intervention during intrauterine device (IUD) insertion based on recent clinical trials in the United States. Methods An electronic search was conducted in the following databases and registry for studies conducted in the United States: Medline via PubMed, SCOPUS, and Clinicaltrials.gov. Data collection occurred between February 7th, 2024, to March 3rd, 2024. Examination of 16 studies, involving 1,524 individuals was utilized in this meta-analysis. Selection criteria included Randomized Controlled Trials (RCT) conducted in the United States, biological women receiving IUDs at the age of 18 years or older, trials comparing treatments to placebo or no treatment, and trials that used the Visual Analogue Scale (VAS) for pain scores. A standard Google Sheets spreadsheet was used to perform data entry. The present review was designed according to the PRISMA guidelines for reporting of systematic reviews incorporating network meta-analyses of health care interventions and was submitted to PROSPERO accordingly (identifier: CRD42024534207). Results We utilized the JADAD scoring guidelines to determine risk of bias assessment through two different reviewers. Network meta-analysis using a random effect model was performed to compare the various pharmacological interventions. The results of the comparison were presented in forest plots and league tables using P-scores and mean differences with 95% confidence intervals. Heterogeneity among studies was assessed by the I² statistic and Cochran’s Q test, and random-effect univariate meta-regression was conducted to explore the source of heterogeneity. Among the four different substances studied, only paracervical lidocaine was significant in producing lower VAS pain scores related to intrauterine device insertion as opposed to placebo (mean difference: -14.6; 95% confidence interval: -27.5, -1.7) and as opposed to oral misoprostol (mean difference: -25.8; 95% confidence interval: -43.8, -7.7). Conclusion Paracervical lidocaine showed the greatest reduction in VAS pain scores during IUD insertion, thus supporting that paracervical lidocaine may be used as a pain management option for future intrauterine device implantation. Future studies should focus on clinical trials utilizing a consistent VAS pain scale and targeting specific subpopulations. Trial Registration: This review has been registered on May 2024 through Prospero with the identifier number: CRD42024534207. Obstetrics & Gynecology Sexual & Reproductive Medicine Analgesia Intrauterine device Pain Pharmacological intervention Paracervical lidocaine Figures Figure 1 Figure 2 Introduction Intrauterine devices (IUDs) are a type of long-acting reversible contraceptives (LARCs) that are inserted into the uterus, intended for a variety of uses such as pregnancy prevention, menorrhagia, anemia, and hormone replacement therapy [ 1 – 3 ] . Despite their proven safety, effectiveness, cost-effectiveness, high satisfaction level and high continuation rates, LARCs are not widely used in the United States, with only 5.5% of women taking contraceptives having an IUD in place [ 2 ] . Pain with IUD insertion continues to be a barrier to its implementation. Pain subjectivity influences its underestimation, contributing to the underemployment of analgesics during IUD insertion by providers [ 4 ] . Consequently, the anticipation of pain discourages IUD use [ 5 ] . This is further complicated by the lack of patient education surrounding the IUD insertion process, leading to misinformation and misrepresentation [ 6 ] . Thus, efforts should be focused on proper education and addressing concerns on its use, meeting patients at their level of health literacy, and facilitating optimal health outcomes [ 7 ] . At this time there is no clear consensus regarding the management of pain experienced by patients during IUD insertion. Rather, there are recommendations based on recent literature. Of which, ACOG recommends the use of topical lidocaine and non-steroidal anti-inflammatory drugs (NSAID) to reduce pain during tenaculum placement and uterine cramping associated with IUD placement, respectively [ 8 , 9 ] . While the Centers for Disease Control and Prevention (CDC) recommends topical or paracervical lidocaine for reducing patient pain during IUD placement [ 10 ] . A prior meta-analysis conducted in 2019 concluded that a lidocaine-prilocaine cream was most effective for pain control during tenaculum placement and IUD insertion [ 11 ] . In contrast, a 2014 meta-analysis reported that paracervical lidocaine provided the greatest reduction in VAS pain scores for these procedures. Collectively, all these findings and recommendations highlight the lack of consistency in treating pain during IUD insertion [ 12 ] . Our study offers a comprehensive and up-to-date meta-analysis focused exclusively on clinical trials conducted within the United States. Our primary focus is on reduction in pain related to the commonly used agents employed during IUD insertion: lidocaine, NSAIDs, misoprostol, and nitric oxide (NO) donors such as nitroglycerine and nitroprusside. Importantly, our secondary analyses uniquely explore the role of patient ethnicity in pain perception during IUD insertion, identifying a potential source of heterogeneity that has not been thoroughly examined in previous reviews. This novel finding may inform future personalized approaches to pain management in gynecologic procedures. The interest in pain management during IUD placement is of high interest with several clinical trials working towards the goal of identifying the most efficacious agents in reducing pain during IUD placement. Methods The present review was designed according to PRISMA guidelines for reporting of systematic reviews incorporating network meta-analyses of health care interventions and was submitted to PROSPERO accordingly in January 2024 (identifier: CRD42024534207) [ 13 ] . As we utilized previously published data from clinical trials, this systematic review and meta-analysis fall under IRB exemption. Study Design Types of studies Only randomized controlled trials (RCTs) with the following criteria were eligible for inclusion in the study: the trials [1] were conducted in the United States, [2] included biological women receiving IUDs at the age of 18 years or older, [3] were compared to placebo treatment or no treatment, and [4] utilized a Visual Analogue Scale (VAS) scoring system. We excluded studies published in languages other than English, head-to-head trials, and studies that were not recruiting yet or were incomplete. Sources An electronic search was conducted in the following databases and registry for studies conducted in the United States: Medline via PubMed, SCOPUS, and Clinicaltrials.gov. Data collection occurred between February 7th, 2024 to March 3rd, 2024. For PubMed searching we used the following queries: (“United states”) AND (“pain management” OR “pain control” OR “anesthetic” OR “anti-inflammatory” OR “non-steroidal” OR “misoprostol” OR “naproxen” OR “toradol” OR “ketorolac” OR “lidocaine” OR “ibuprofen” OR “nitroglycerin” OR “nitrous oxide” OR “nitroprusside”) AND “(IUD insertion” OR “intrauterine device” OR “IUD”). For SCOPUS searching we used the following queries: (“pain” OR “pain” AND “management” OR “pain” AND “control” OR “anesthetic” OR “anti-inflammatory” OR “non-steroidal”) AND (“misoprostol” OR “naproxen” OR “toradol” OR “ketorolac” OR “lidocaine” OR “ibuprofen” OR “nitroglycerin” OR “nitrous” AND “oxide” OR “nitroprusside”) AND (“intrauterine” AND “device” OR “iud”) AND (“United States”). For clinicaltrials.gov we used the following queries: [Condition: “IUD Insertion”; Intervention: “pain”; Location: “USA”]. We retrieved and imported citations into a Google Sheets spreadsheet for screening, utilizing the inclusion and exclusion criteria mentioned previously. Four independent reviewers conducted screening of citations by reviewing abstracts followed by a full-text screening of eligible records. Data extraction We utilized a Google Sheets spreadsheet to perform data entry in which four reviewers extracted data from the included studies. The data included the following information for both the treatment group and the placebo group: [1] intervention, [2] dosage, [3] route of delivery, [4] number of participants, [5] mean age of participants, [6] VAS range, [7] patient reported pain via the VAS for speculum insertion, tenaculum placement, during IUD insertion, post-IUD insertion, and prior to discharge, [8] provider ease, [9] race/ethnicity, and [10] parity. All reviewers worked independently to extract data from the included studies, followed by a final review of all study data by a single reviewer. Outcome definitions Pain outcomes, as measured by a VAS scoring system at the time of IUD insertion, were defined as our primary outcome. Pain outcomes at the time of speculum insertion, tenaculum placement, post-IUD insertion, prior to discharge, and provider-perceived ease of placement were defined as secondary outcomes. Risk of bias assessment We utilized the JADAD scoring guidelines to determine risk of bias assessment [ 14 ] . Two reviewers separately assessed all studies in our review and scored each based on the following criteria: the study was [1] randomized, [2] double blinded, and [3] accounted for withdrawals and dropouts. Additional points were given to those studies that described the method of randomization as well as the method of blinding. Points were withdrawn from those studies that used inappropriate methods of randomization or blinding. Statistical analysis A network meta-analysis was conducted to compare the pharmacological interventions across studies. A random-effect model was assumed when pooling the study outcomes. Before pooling, all VAS scores were converted to a scale of 0-100. When mean or standard deviation (SD) were not reported, they were approximated by median and interquartile range (IQR) using Method 4 in Greco et al 2015, or range using the formula in Hozo et al 2005 [ 15 , 16 ] . The results of the network meta-analysis were presented in [1] network geometry, [2] a forest plot, and [3] a league table. Network geometry showed the structure of evidence, where each treatment was represented by a node, the thickness of a linkage between every two nodes indicated the number of studies directly comparing the two treatments, and the size of a node indicated the combined sample size for each treatment. The forest plot included a P -score on a scale of zero to one for each treatment that can be interpreted as the likelihood of that treatment being the best option. While P -scores provided a relative ranking of the treatments, they did not necessarily infer a significant difference between any two treatments. To further examine the significance of the difference, we referred to the mean differences (MD) and 95% confidence intervals (CI) in the forest plot for the comparison between each treatment and placebo, and the league table for the comparison between one pharmacological treatment to another pharmacological treatment. A 95% CI that did not cross zero indicated a significant difference. Heterogeneity among studies was assessed by the I² statistic and Cochran’s Q test. Consistency between direct and indirect evidence was not assessed since in all included studies, the pharmacological treatments were compared to placebo or no treatment. In the presence of heterogeneity, random-effect univariate meta-regression was conducted to explore the potential source of heterogeneity among studies, e.g. mean age, ratio of nulliparous participants, ratio of Caucasian participants, ratio of African American participants, ratio of Hispanic participants, route of delivery, JADAD score, and VAS range. We included this in our paper to highlight potential disparities in pain perception and overall pain experiences to ensure a more comprehensive approach to reproductive healthcare. Finally, the presence of publication bias was assessed by the funnel plot and Egger test. Meta-regressions, funnel plots, and Egger tests were only performed for outcomes with 10 or more studies. All statistical analyses were performed in R v.4.1.2 and package netmeta and meta were used for the network meta-analysis and meta-regression, respectively. P value < 0.05 was considered significant. Results Literature Search The literature search identified a total of 397 citations. After the PRISMA selection process, 16 trials remained for data extraction. The flow diagram in Fig. 1 describes the selection process. Study characteristics and demographic data are presented in Table 1 . Table 1 Descriptive characteristics of United States Clinical Trials evaluating pain with IUD insertion from 2011–2024 Author, Year Study Type Jadad Score Substance Dosage Route of Delivery Placebo Participant # in Trial Participant # in TG Participant # in PG Mean age (TG) Mean age (PG) Eligibility Parity (TG) Parity (PG) Berens, 2018 RCT 2 Lidocaine 1%, Unknown Paracervical block No analgesia 50 25 25 24.6 ± 4.6 26.6 ± 5.9 F 18–52 y/o 3 NP 22 MP 25 MP Micks, 2014 QB-RCT 5 NO Donor - Nitroglycerin Unknown Vaginally Placebo Ointment 24 12 12 28.3 ± 6.9 25.7 ± 4.4 F 18–45 y/o 12 NP 12 NP Lathrop, 2013 TB-RCT 5 Misoprostol 400 mcg Orally (buccally) Identical pill 78 35 36 26.05 ± 0.554 25.5 ± 0.554 F 18–45 y/o 35 NP 36 NP Bednarek, 2013 DB-RCT 5 NO Donor - Nitroprusside 10 mg, 1 mL Vaginally Placebo gel 24 13 11 24.2 ± 4.4 24.4 ± 4.0 F 18–45 y/o 13 NP 11 NP Allen, 2013 QB-RCT 5 Lidocaine 2%, 120 mg Vaginally Inert gel 150 72 73 26.2 ± 5.3 25.2 ± 5 F 18–49 y/o 3 NP 69 MP (11 C, 58 V) 5 NP 68 MP (17 C, 51 V) Swenson, 2012 TB-RCT 5 Misoprostol 400 mcg Vaginally or Buccally Identical pill 108 54 51 24.6 ± 3.8 24.8 ± 4.2 F 18 y/o or older 54 NP 51 NP Conti, 2019 DB-RCT 5 Lidocaine 2%, 10 mL Vaginally Surgical Lubricant Jelly 220 108 107 MD = 28.9 range (18–48) MD = 27.0 range (18–51) F 18 y/o or older 83 NP 11 C 79 NP 6 C Mody, 2018 SB-RCT 5 Lidocaine 1%, 18 mL Paracervical block Sham block 67 33 31 26.1 ± 3.9 24.8 ± 3.4 F 18–45 y/o 33 NP 31 NP Maguire, 2012 TB-RCT 5 Lidocaine 2%, 1 mL Vaginally Surgilube gel 200 100 100 27.1 ± 6 27.6 ± 6 F 18–45 y/o 39 NP 61 P (18 C, 43 V) 21 NP 79 P (16 C, 63 V) Mody, 2012 RCT 2 Lidocaine 1%, 10 cc Paracervical block None 50 26 24 31.9 ± 5.9 33.2 ± 6.2 F 18–50 y/o 9 NP 17 MP 8 NP 16 MP Ngo, 2015 QB-RCT 5 NSAID - Toradol 30 mg in 1 cc Intramuscular injection Normal saline 67 33 34 26.6 ± 5.1 27.3 ± 5.4 F 18–50 y/o 8 NP 25 MP 8 NP 26 MP McNicholas, 2012 QB-RCT 5 Lidocaine 2%, 3–5 cc Vaginally Water based lubricant 200 100 99 N/A N/A F 18–45 y/o 50 NP 50 MP 50 NP 49 MP Ngo, 2016 TB-RCT 5 NSAID - Naproxen Sodium 550 mg Orally Placebo tablet 119 58 60 23.2 ± 3.9 24.3 ± 4.2 F 18 y/o or older 57 NP 1 P 58 NP 2 P Edelman, 2011 QB-RCT 5 Misoprostol 400 mcg Orally (Buccally) Placebo pill 40 17 18 25 ± 5 27 ± 6 F 18–45 y/o 17 NP 18 NP Chor, 2012 DB-RCT 5 NSAID - Ibuprofen 800 mg Orally Placebo pill 87 44 37 24.66 ± 5.4 27.89 ± 6.5 F 18 y/o or older 3 NP 41 MP 0 NP 37 MP Nelson, 2013 TB-RCT 5 Lidocaine 2%, 1.3 cc Endometrial Infusion Normal saline 40 20 20 32.05 range (20–43) 32.06 range (19–46) F 18–50 y/o N/A N/A F = Female, NP = Nulliparous, MP = Multiparous, P = Parous, C = Cesarean, V = Vaginal, TG = Treatment Group, PG = Placebo Group, RCT = Randomized Controlled Trials, QB = Quadruple blinding, TB = Triple Blinded DB = Double Blinded, MD = Median Characteristics of studies Of the included studies, eight assessed the use of lidocaine during IUD insertion. Four of these studies applied lidocaine gel vaginally to the cervix while the placebo arm used a placebo gel, in both nulliparous and multiparous participants [ 17 – 20 ] . Three studies performed paracervical blocks with lidocaine; two were against no treatment in both nulliparous and multiparous participants and one was against a sham paracervical block in nulliparous individuals only [ 21 – 23 ] . The remaining study assessed the use of lidocaine endometrial infusion during IUD insertion versus normal saline endometrial infusion [ 24 ] . The use of NSAIDs (Toradol, Naproxen Sodium & Ibuprofen) during IUD insertion was assessed in three studies. Two of which used an oral route of delivery while the other performed through intramuscular (IM) injection against placebo tablets and saline injection, respectively, in both nulliparous and multiparous individuals [ 25 – 27 ] . Misoprostol was studied in three clinical trials and administered buccally in nulliparous individuals only. However, one trial gave patients the choice between buccal or vaginal administration. All trials utilized an identical tablet in the placebo arm [ 28 – 30 ] . Nitric oxide (NO) donors were studied in two clinical trials, specifically nitroglycerin and nitroprusside. Both NO donors were in the form of a gel and administered vaginally to the cervix in nulliparous individuals only [ 5 , 31 ] . Most of the studies included assessing patient-reported pain during IUD insertion using the VAS, with scores ranging from 0-100. There were four studies that utilized the VAS with a range of 0–10; one from the NSAID group and three from the lidocaine group, while the lidocaine endometrial infusion trial utilized a VAS with a range of 0–9 [ 20 , 22 , 25 ] . Additionally, the mean and SD of the VAS were reported in most of the studies. There were six studies that reported median, two of which were accompanied by IQR (one from the IM NSAID group and one from the oral NSAID group), and three with range only (two from the vaginal lidocaine group and one from the oral misoprostol group) [ 19 – 21 , 25 , 26 , 28 ] . It is to be noted that McNicholas 2012 reported median and range only while utilizing the VAS with a range of 0–10 [ 20 ] . The mean and SD were converted and approximated before pooling, therefore, interpretation of the results involving this study should be made with caution. The quality of randomization and blinding of the discussed clinical trials were assessed by the JADAD scoring guidelines and documented in Table 1 . 14 of the 16 studies scored a maximum of five out of five points, indicating the studies are of high quality. The other two studies scored a two out of five as there was no placebo arm, the method of randomization was not specified, and both patients and investigators were unblinded [ 22 , 23 ] . Primary outcomes IUD insertion 16 studies with 1,488 biological women were included in the IUD insertion network. As shown in Fig. 2 , P-scores associated with each substance studied during IUD insertion were generated with paracervical lidocaine having the largest likelihood of being the best treatment option ( P -score = 0.85) and oral misoprostol having the smallest likelihood of being the best treatment option ( P -score = 0.08). Paracervical lidocaine was associated with significantly greater pain reduction than placebo (MD: -14.6; 95% CI: -27.5, -1.7) and oral misoprostol (MD: -25.8; 95% CI: -43.8, -7.7). The differences between other treatment options were not significant. The heterogeneity among studies was significant (I 2 = 70%, P = 0.001). Based on the univariate meta-regression (Table 2 ), the VAS pain scale (71.9%), route of delivery (43.6%), ratio of African American women (20.7%), JADAD scores (15.8%), and ratio of nulliparous women (15.5%) were likely to be responsible for the heterogeneity, comparing to mean age, ratio of Caucasian women, and ratio of Hispanic women (all 0%). Studies using 0-100 VAS pain scale reported significantly less pain reduction than studies using 0–10 (or 0–9) VAS pain scale ( P = 0.01). Studies using other routes of delivery (IM, intrauterine, paracervical) reported greater pain reduction than studies using orally route of delivery, regardless of the substance used ( P = 0.004). Although statistically insignificant ( P > 0.05 ), studies with higher ratios of nulliparous women may be reporting less pain reduction, and studies with higher ratios of African American women may be reporting greater pain reduction. It is to be noted in the bubble plot (Figure s1) that McNicholas 2012, a large study that reported median and range only using a 0–10 VAS, apparently deviates away from the regression line between ratio of nulliparous women and mean VAS differences [ 20 ] . This study, together with the small number of studies available for meta-regression, may be causing the relationship to appear insignificant. However, the trend should not be ignored, and further investigation is warranted. For the evaluation of publication bias, while there may be some visible asymmetry in the funnel plot (Figure s2), Egger’s test did not reach statistical significance ( P = 0.23). For the sensitivity analysis, we excluded McNicholas 2012 from the IUD insertion network and found paracervical lidocaine to still have the largest likelihood of being the best treatment option while oral misoprostol had the smallest likelihood. Table 2 Univariate Meta-Regression: assessment of covariates associated with pain reduction during IUD Insertion Covariate IUD Insertion n Regression Coefficient (95% CI) P Value Heterogeneity Explained By Covariate (%) Mean Age 15 -0.9 (-2.8 to 1.0) 0.36 0.0% Ratio of Caucasian Women 15 6.6 (-9.1 to 22.3) 0.41 0.0% Ratio of African American Women 10 -18.0 (-49.0 to 13.0) 0.26 20.7% Ratio of Hispanic Women 11 2.9 (-25.9 to 31.7) 0.84 0.0% Ratio of Nulliparous Women 15 7.4 (-3.8 to 18.6) 0.20 15.5% Route of Delivery 16 -- 0.004* 43.6% Orally 4 reference reference -- Vaginally 7 -8.5 (-17.3 to 0.3) 0.06 -- Other (Intramuscular, Intrauterine, Paracervical) 5 -20.6 (-32.7 to -8.5) 0.001* -- JADAD Score 16 4.0 (-0.9 to 8.9) 0.11 15.8% VAS Pain Scale 16 -- 0.01* 71.9% 0-100 11 reference reference -- 0–10 (or 0–9) 5 -9.6 (-16.6 to -2.7) 0.01* -- Secondary outcomes The results of the network meta-analysis for the secondary outcomes can be found in Figure s3-s7. NSAIDs (IM) had the largest likelihood of being the best treatment option in reducing pain during speculum insertion, tenaculum placement, post-IUD insertion, and prior to discharge ( P -score = 0.89, 0.80, 0.85, and 0.87, respectively). However, most of the differences were not significant, except for the pain prior to discharge. Greater pain reduction was perceived prior to discharge if NSAIDs (IM) were used as opposed to lidocaine (vaginally), placebo, or misoprostol (both routes). On the other hand, vaginal misoprostol had the largest likelihood of being the best option in increasing provider ease ( P -score = 0.89), and was significantly better than placebo (MD: -2.3; 95% CI: -3.6, -1.0). Significant heterogeneity was only detected in the tenaculum placement network (I 2 = 60%, P = 0.02). The results of the univariate meta-regression for tenaculum placement can be found in Table s1 and Figure s8. No significant relationship was found, but mean age and ratio of Hispanic individuals account for 48.7% and 34.6% of the heterogeneity, respectively. Although insignificant, studies with participants of higher mean age may be reporting greater pain reduction during tenaculum placement, and studies with higher ratios of Hispanic individuals may be reporting less pain reduction. Since older individuals are more likely to be multiparous, this trend is consistent with the trend observed in IUD insertion. For the evaluation of publication bias, while there may be some visible asymmetry in the funnel plot (Figure s9), Egger’s test did not reach statistical significance ( P = 0.75). Discussion This review revealed that paracervical lidocaine was the most effective pharmacological pain management intervention with IUD insertion, shown through lower VAS pain scores. Specifically, paracervical lidocaine was shown to be a better intervention for pain management than oral misoprostol and placebo groups, consistent with findings in previous literature against placebos [ 12 ] . This study systematically compares analgesics and their various routes of administration from United States clinical trials, including NSAIDs (administered orally and IM), lidocaine (administered intrauterine and vaginally), misoprostol (administered orally and vaginally), NO donors (administered vaginally), and placebo, further emphasizing the usefulness of this study in clinical practice. Our data highlights that the IUD insertion process is a multifaceted and personalized procedure influenced by patient characteristics, provider preferences, and pain management options. The provider preference, typically determined by ease, can conflict with what may be better suited for pain management for the patient, further exacerbating individualized pain management. We identified that the preferential method for providers during IUD insertion was utilizing vaginal misoprostol over the placebo treatment. The rational for using misoprostol is that by both dilating and softening the cervix, it can facilitate an easier IUD insertion for the provider, which may result in a less painful experience for the patient [ 32 ] . There were no significant differences among pharmacological treatments for speculum insertion, tenaculum placement, and post IUD insertion noted in our data analysis. However, our findings indicated several significant differences between pharmacological pain management options for pain prior to discharge, with NSAIDS (IM) yielding the greatest pain reduction perceived prior to discharge. Furthermore, this study reinforces the various patient characteristics that influence pain, ranging from age and ethnic background to parity. Previous studies have reported greater pain in people older than 30 years of age, nulliparous individuals, and patients with a history of dysmenorrhea [ 17 , 33 ] . In our meta-analysis, the ratio of nulliparous and African American individuals explained 20.7% and 15.5% of the heterogeneity seen in the resultant pain reduction during IUD insertion respectively, which suggests their influence on pain consistently across studies. With the analysis of data from 16 clinical trials, we have provided an updated network meta-analysis on pharmacological pain management for IUD insertion. This contributes to a growing body of data and provides a foundation for future research by identifying gaps in existing literature that can be further examined. Limitations A challenging limitation to address, yet appreciated as a factor in pain perception, is the subjectivity and complexity of pain. Nulliparity, ethnicities, past medical history, including histories of sexually transmitted infections (STIs) and pelvic inflammatory disease (PID), and type of IUD all play a role in pain. As a result of this limited information, we were unable to stratify these confounders when evaluating pain. There may even be other confounders that are not appreciated in the perception of pain that need to be further investigated, such as the patient's anxiety and experience with having an IUD placed, a negative perception of IUDs, ovulation cycle timing, and age at IUD placement. In fact, a recent study in 2019 showed that the negative perception of IUDs was the strongest predictor of pain with IUD insertion in parous women [34] . Thus, the subjective nature of pain limits our ability to sufficiently generalize pain reduction. Our inclusion criteria was an additional limiting factor to our study. We solely used the VAS to quantify pain, thus simplifying a qualitative experience for the sake of data extraction and interpretation. The inclusion of biological women at or above the age of 18 years old also reduced the ability to generalize our results. The rationale for excluding individuals under the age of 18 years old was intended to minimize variables that impact pain scores that may be reported by adolescents. In the United States, adolescents do not typically undergo routine pelvic examinations until the age of 21 years old, thus, the insertion of an IUD may be their first experience with a gynecologic procedure which may increase both the anticipation of pain and pain during the procedure [ 35 , 36 ] . By conducting a network meta-analysis, the results of this study can apply to a more diverse patient population. However, due to the small number of studies available, the meta-regression was underpowered in detecting significant effect modifiers. External validity is also constrained by the limited number of participants in the clinical trials, and our exclusive utilization of trials conducted in the United States. International data may provide a different perspective on the influences that determine pain. We recognize that this comparison relies on the availability of relevant information based on published current trials. Since our study relied on clinical trials that had accessible results, we were subjected to the pharmacological agents used in the trials as the basis of our meta-analysis. Thus, there could be many other pharmacological agents utilized in clinical trials that were not evaluated due to results not being posted at the time of discovery or because the trials were not listed on the registry that may provide additional pain reduction. Future research In general, our study found that multiparous women and older women may experience greater pain reduction, and that the treatments seemed less effective for both nulliparous and younger women. Additionally, nulliparous women reported greater pain in comparison to multiparous women with IUD placement, likely due to the absence of cervical dilation that results after childbirth in multiparous women [ 25 , 33 , 37 ] . This suggests an implication to increase medication dosages in both nulliparous and younger women, prompting an investigation of this potential benefit in future studies. Ethnic minorities such as African American and Hispanic patients have historically been undertreated for pain due to systemic inequalities, leading them to report greater pain and contributing to health disparities amongst these racial groups [ 38 – 40 ] . Because our analysis identified ethnicity as a potential influencing factor in pain, future research should explore this role; a new, holistic approach to pain management that has yet to be appreciated. Such research will enable the development of culturally competent interventions and improve pain mitigation strategies. Conclusion The purpose of this meta-analysis was to evaluate the pharmacologic pain management options during IUD insertion and to provide an update on the current literature. Our findings suggest that paracervical lidocaine may be the most effective pharmacological intervention for pain management during an IUD insertion, as indicated by comparatively lower VAS pain scores. Accordingly, it is reasonable to suggest that providers consider the use of paracervical lidocaine as a potential pain management option for IUD insertion. In contrast, oral misoprostol was the least effective in lowering patient VAS pain scores during IUD insertion. Future studies should be directed towards larger sample sizes and facilitation towards robust multivariate meta-regression analyses to understand and stratify the role of the variables that affect pain. Declarations Ethics approval and consent to participant : Formal ethical approval was not required as this study was a systematic review and network meta-analysis. Consent for publication: Not Applicable Availability of data and materials: All data generated or analyzed during this study are included in this published article and supplementary materials. Competing interests : The authors declare that they have no competing interests. Funding: There has been no financial incentive for conducting this study. Authors’ contributions: JT registered the study. JT and KB were primary contributors in the writing of the manuscript as well as the literature search. BP and JT contributed to the introduction. JT and DB contributed to the study design. MW and AW conducted the statistical analysis and data extraction, including the random-effect univariate meta-regression and assessment of publication bias through the funnel plot and Egger tests; MW and AW reported on these outcomes through primary and secondary outcomes. AH and BP created the figure1 and table 1 based on our data and contributed to the discussion with KB. DB provided oversight for the systematic approach and ensured adherence to PRISMA guidelines. RH provided oversight on the clinical significance of our findings and provided a medical background on IUD use. All authors read and approved the final manuscript. Acknowledgements : Not applicable References Centers for Disease Control and Prevention. “Contraception.” Reproductive Health. Published 28 May 2024, www.cdc.gov/reproductive-health/contraception/?CDC_AAref_Val=www.cdc.gov/reproductivehealth/contraception/index.htm. Accessed 29 Apr., 2024. Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol . 2011;117(5):1105-1113. doi:10.1097/AOG.0b013e31821188ad. Accessed 24 May, 2024. Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv . 2002;57(2):120-128. doi:10.1097/00006254-200202000-00024 Akintomide H, Brima N, Sewell RD, Stephenson JM. Patients' experiences and providers' observations on pain during intrauterine device insertion. Eur J Contracept Reprod Health Care. 2015;20(4):319-326. doi:10.3109/13625187.2015.1031885. Accessed 12 Apr., 2024. Bednarek PH, Micks EA, Edelman AB, Li H, Jensen JT. The effect of nitroprusside on IUD insertion experience in nulliparous women: a pilot study. Contraception. 2013;87(4):421-425. doi:10.1016/j.contraception.2012.10.030. Accessed 12 Apr., 2024. Phillips J, Sandhu P. Barriers to implementation of long-acting reversible contraception: A systematic review. J Am Assoc Nurse Pract . 2018;30(4):236-243. doi:10.1097/JXX.0000000000000019. Accessed 12 Apr., 2024 Protheroe J, Nutbeam D, Rowlands G. Health literacy: a necessity for increasing participation in health care. Br J Gen Pract . 2009;59(567):721-723. doi:10.3399/bjgp09X472584. Accessed 23 May, 2024. Estevez E, Hem-Lee-Forsyth S, Viechweg N, John S, Menor SP. Advancing Pain Management Protocols for Intrauterine Device Insertion: Integrating Evidence-Based trategies Into Clinical Practice. Cureus . 2024;16(6):e63125. Published 2024 Jun 25. doi:10.7759/cureus.63125. Accessed 23 Sept., 2024. American College of Obstetricians and Gynecologists. Managing pain with IUD insertion. American College of Obstetricians and Gynecologists. Published December 2020. Accessed 16 Apr., 2024. https://www.acog.org/programs/long-acting-reversible-contraception-larc/video-series/insertion/managing-pain-with-iud-insertion Curtis KM, Nguyen AT, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2024. MMWR Recomm Rep 2024;73(No. RR-3):1–77. DOI: http://dx.doi.org/10.15585/mmwr.rr7303a1 Samy A, Abbas AM, Mahmoud M, et al. Evaluating different pain lowering medications during intrauterine device insertion: a systematic review and network meta-analysis. Fertil Steril . 2019;111(3):553-561.e4. doi:10.1016/j.fertnstert.2018.11.012 Pergialiotis V, Vlachos DG, Protopappas A, Vlachos GD. Analgesic options for placement of an intrauterine contraceptive: a meta-analysis. Eur J Contracept Reprod Health Care . 2014;19(3):149-160. doi:10.3109/13625187.2014.903238. Accessed 23 May, 2024. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2020;372:n71. Accessed 1 May, 2024. 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Higher dose cervical 2% lidocaine gel for IUD insertion: a randomized controlled trial. Contraception . 2013;88(6):730-736. doi:10.1016/j.contraception.2013.07.009. Accessed 7 Feb., 2024. Conti JA, Lerma K, Schneyer RJ, Hastings CV, Blumenthal PD, Shaw KA. Self-administered vaginal lidocaine gel for pain management with intrauterine device insertion: a blinded, randomized controlled trial. Am J Obstet Gynecol . 2019;220(2):177.e1-177.e7. doi:10.1016/j.ajog.2018.11.1085. Accessed 7 Feb., 2024. McNicholas CP, Madden T, Zhao Q, Secura G, Allsworth JE, Peipert JF. Cervical lidocaine for IUD insertional pain: a randomized controlled trial. Am J Obstet Gynecol . 2012;207(5):384.e1-384.e3846. doi:10.1016/j.ajog.2012.09.018. Accessed 7 Feb., 2024. Mody SK, Farala JP, Jimenez B, Nishikawa M, Ngo LL. Paracervical Block for Intrauterine Device Placement Among Nulliparous Women: A Randomized Controlled Trial. Obstet Gynecol . 2018;132(3):575-582. doi:10.1097/AOG.0000000000002790. Accessed 7 Feb., 2024. Berens P. Paracervical block versus no paracervical block during IUD insertion. ClinicalTrials.gov . Identifier: NCT02904915. Available at: https://clinicaltrials.gov/ct2/show/NCT02904915. Accessed 7 Feb., 2024. Mody SK, Kiley J, Rademaker A, Gawron L, Stika C, Hammond C. Pain control for intrauterine device insertion: a randomized trial of 1% lidocaine paracervical block. Contraception . 2012;86(6):704-709. doi:10.1016/j.contraception.2012.06.004. Accessed 7 Feb., 2024. Nelson AL, Fong JK. Intrauterine infusion of lidocaine does not reduce pain scores during IUD insertion. Contraception . 2013;88(1):37-40. doi:10.1016/j.contraception.2012.12.009. Accessed 7 Feb., 2024. Ngo LL, Ward KK, Mody SK. Ketorolac for Pain Control With Intrauterine Device Placement: A Randomized Controlled Trial. Obstet Gynecol . 2015;126(1):29-36. doi:10.1097/AOG.0000000000000912. Accessed 7 Feb., 2024. Ngo LL, Braaten KP, Eichen E, Fortin J, Maurer R, Goldberg AB. Naproxen Sodium for Pain Control With Intrauterine Device Insertion: A Randomized Controlled Trial. Obstet Gynecol . 2016;128(6):1306-1313. doi:10.1097/AOG.0000000000001746. Accessed 7 Feb., 2024. Chor J, Bregand-White J, Golobof A, Harwood B, Cowett A. Ibuprofen prophylaxis for levonorgestrel-releasing intrauterine system insertion: a randomized controlled trial. Contraception . 2012;85(6):558-562. doi:10.1016/j.contraception.2011.10.015. Accessed 7 Feb., 2024. Lathrop E, Haddad L, McWhorter CP, Goedken P. Self-administration of misoprostol prior to intrauterine device insertion among nulliparous women: a randomized controlled trial. Contraception . 2013;88(6):725-729. doi:10.1016/j.contraception.2013.07.011. Accessed 7 Feb., 2024. Swenson C, Turok DK, Ward K, Jacobson JC, Dermish A. Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. Obstet Gynecol . 2012;120(2 Pt 1):341-347. doi:10.1097/AOG.0b013e31825d9ec9. Accessed 7 Feb., 2024. Edelman AB, Schaefer E, Olson A, et al. Effects of prophylactic misoprostol administration prior to intrauterine device insertion in nulliparous women. Contraception . 2011;84(3):234-239. doi:10.1016/j.contraception.2011.01.016. Accessed 7 Feb., 2024. Micks EA, Jensen JT, Bednarek PH. The effect of nitroglycerin on the IUD insertion experience in nulliparous women: a pilot study. Contraception . 2014;90(1):60-65. doi:10.1016/j.contraception.2014.03.012. Accessed 7 Feb., 2024. Zapata LB, Nguyen A, Snyder E, et al. Misoprostol for intrauterine device placement. Cochrane Database Syst Rev . 2022;2022(7):CD015584. Published 2022 Jul 21. doi:10.1002/14651858.CD015584. Hubacher D, Reyes V, Lillo S, Zepeda A, Chen PL, Croxatto H. Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. Am J Obstet Gynecol . 2006;195(5):1272-1277. doi:10.1016/j.ajog.2006.08.022. Accessed 1 Apr., 2024. ‌ Akdemir Y, Karadeniz M. The relationship between pain at IUD insertion and negative perceptions, anxiety and previous mode of delivery. The European Journal of Contraception & Reproductive Health Care . 2019;24(3):240-245. doi:https://doi.org/10.1080/13625187.2019.1610872. Accessed 1 Apr., 2024. Brima N, Akintomide H, Iguyovwe V, Mann S. A comparison of the expected and actual pain experienced by women during insertion of an intrauterine contraceptive device. Open Access J Contracept . 2015;6:21-26. Published 2015 Feb 16. doi:10.2147/OAJC.S74624. Mutch DG. Why annual pap smears are history – but routine OB-GYN visits are not. ACOG. Accessed May 3, 2025. https://www.acog.org/womens-health/experts-and-stories/the-latest/why-annual-pap-smears-are-history-but-routine-ob-gyn-visits-are-not. Chi IC, Galich LF, Tauber PF, et al. Severe pain at interval IUD insertion: a case-control analysis of patient risk factors. Contraception . 1986;34(5):483-495. doi:10.1016/0010-7824(86)90057-0. Accessed 1 Apr., 2024. Hoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proc Natl Acad Sci U S A . 2016;113(16):4296-4301. doi:10.1073/pnas.1516047113. Accessed 1 May, 2024. Mossey JM. Defining racial and ethnic disparities in pain management. Clin Orthop Relat Res . 2011;469(7):1859-1870. doi:10.1007/s11999-011-1770-9. Accessed 1 Apr., 2024. Reyes-Gibby CC, Aday LA, Todd KH, Cleeland CS, Anderson KO. Pain in aging community-dwelling adults in the United States: non-Hispanic whites, non-Hispanic blacks, and Hispanics. J Pain . 2007;8(1):75-84. doi:10.1016/j.jpain.2006.06.002. Accessed 1 Apr., 2024. Additional Declarations The authors declare no competing interests. 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Despite their proven safety, effectiveness, cost-effectiveness, high satisfaction level and high continuation rates, LARCs are not widely used in the United States, with only 5.5% of women taking contraceptives having an IUD in place \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePain with IUD insertion continues to be a barrier to its implementation. Pain subjectivity influences its underestimation, contributing to the underemployment of analgesics during IUD insertion by providers \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Consequently, the anticipation of pain discourages IUD use \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. This is further complicated by the lack of patient education surrounding the IUD insertion process, leading to misinformation and misrepresentation \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Thus, efforts should be focused on proper education and addressing concerns on its use, meeting patients at their level of health literacy, and facilitating optimal health outcomes \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAt this time there is no clear consensus regarding the management of pain experienced by patients during IUD insertion. Rather, there are recommendations based on recent literature. Of which, ACOG recommends the use of topical lidocaine and non-steroidal anti-inflammatory drugs (NSAID) to reduce pain during tenaculum placement and uterine cramping associated with IUD placement, respectively \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. While the Centers for Disease Control and Prevention (CDC) recommends topical or paracervical lidocaine for reducing patient pain during IUD placement \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. A prior meta-analysis conducted in 2019 concluded that a lidocaine-prilocaine cream was most effective for pain control during tenaculum placement and IUD insertion \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In contrast, a 2014 meta-analysis reported that paracervical lidocaine provided the greatest reduction in VAS pain scores for these procedures. Collectively, all these findings and recommendations highlight the lack of consistency in treating pain during IUD insertion \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study offers a comprehensive and up-to-date meta-analysis focused exclusively on clinical trials conducted within the United States. Our primary focus is on reduction in pain related to the commonly used agents employed during IUD insertion: lidocaine, NSAIDs, misoprostol, and nitric oxide (NO) donors such as nitroglycerine and nitroprusside. Importantly, our secondary analyses uniquely explore the role of patient ethnicity in pain perception during IUD insertion, identifying a potential source of heterogeneity that has not been thoroughly examined in previous reviews. This novel finding may inform future personalized approaches to pain management in gynecologic procedures. The interest in pain management during IUD placement is of high interest with several clinical trials working towards the goal of identifying the most efficacious agents in reducing pain during IUD placement.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe present review was designed according to PRISMA guidelines for reporting of systematic reviews incorporating network meta-analyses of health care interventions and was submitted to PROSPERO accordingly in January 2024 (identifier: CRD42024534207)\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. As we utilized previously published data from clinical trials, this systematic review and meta-analysis fall under IRB exemption.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eTypes of studies\u003c/h2\u003e \u003cp\u003eOnly randomized controlled trials (RCTs) with the following criteria were eligible for inclusion in the study: the trials [1] were conducted in the United States, [2] included biological women receiving IUDs at the age of 18 years or older, [3] were compared to placebo treatment or no treatment, and [4] utilized a Visual Analogue Scale (VAS) scoring system. We excluded studies published in languages other than English, head-to-head trials, and studies that were not recruiting yet or were incomplete.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eSources\u003c/h3\u003e\n\u003cp\u003eAn electronic search was conducted in the following databases and registry for studies conducted in the United States: Medline via PubMed, SCOPUS, and Clinicaltrials.gov. Data collection occurred between February 7th, 2024 to March 3rd, 2024.\u003c/p\u003e \u003cp\u003eFor PubMed searching we used the following queries: (\u0026ldquo;United states\u0026rdquo;) AND (\u0026ldquo;pain management\u0026rdquo; OR \u0026ldquo;pain control\u0026rdquo; OR \u0026ldquo;anesthetic\u0026rdquo; OR \u0026ldquo;anti-inflammatory\u0026rdquo; OR \u0026ldquo;non-steroidal\u0026rdquo; OR \u0026ldquo;misoprostol\u0026rdquo; OR \u0026ldquo;naproxen\u0026rdquo; OR \u0026ldquo;toradol\u0026rdquo; OR \u0026ldquo;ketorolac\u0026rdquo; OR \u0026ldquo;lidocaine\u0026rdquo; OR \u0026ldquo;ibuprofen\u0026rdquo; OR \u0026ldquo;nitroglycerin\u0026rdquo; OR \u0026ldquo;nitrous oxide\u0026rdquo; OR \u0026ldquo;nitroprusside\u0026rdquo;) AND \u0026ldquo;(IUD insertion\u0026rdquo; OR \u0026ldquo;intrauterine device\u0026rdquo; OR \u0026ldquo;IUD\u0026rdquo;).\u003c/p\u003e \u003cp\u003eFor SCOPUS searching we used the following queries: (\u0026ldquo;pain\u0026rdquo; OR \u0026ldquo;pain\u0026rdquo; AND \u0026ldquo;management\u0026rdquo; OR \u0026ldquo;pain\u0026rdquo; AND \u0026ldquo;control\u0026rdquo; OR \u0026ldquo;anesthetic\u0026rdquo; OR \u0026ldquo;anti-inflammatory\u0026rdquo; OR \u0026ldquo;non-steroidal\u0026rdquo;) AND (\u0026ldquo;misoprostol\u0026rdquo; OR \u0026ldquo;naproxen\u0026rdquo; OR \u0026ldquo;toradol\u0026rdquo; OR \u0026ldquo;ketorolac\u0026rdquo; OR \u0026ldquo;lidocaine\u0026rdquo; OR \u0026ldquo;ibuprofen\u0026rdquo; OR \u0026ldquo;nitroglycerin\u0026rdquo; OR \u0026ldquo;nitrous\u0026rdquo; AND \u0026ldquo;oxide\u0026rdquo; OR \u0026ldquo;nitroprusside\u0026rdquo;) AND (\u0026ldquo;intrauterine\u0026rdquo; AND \u0026ldquo;device\u0026rdquo; OR \u0026ldquo;iud\u0026rdquo;) AND (\u0026ldquo;United States\u0026rdquo;).\u003c/p\u003e \u003cp\u003eFor clinicaltrials.gov we used the following queries: [Condition: \u0026ldquo;IUD Insertion\u0026rdquo;; Intervention: \u0026ldquo;pain\u0026rdquo;; Location: \u0026ldquo;USA\u0026rdquo;].\u003c/p\u003e \u003cp\u003eWe retrieved and imported citations into a Google Sheets spreadsheet for screening, utilizing the inclusion and exclusion criteria mentioned previously. Four independent reviewers conducted screening of citations by reviewing abstracts followed by a full-text screening of eligible records.\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eWe utilized a Google Sheets spreadsheet to perform data entry in which four reviewers extracted data from the included studies. The data included the following information for both the treatment group and the placebo group: [1] intervention, [2] dosage, [3] route of delivery, [4] number of participants, [5] mean age of participants, [6] VAS range, [7] patient reported pain via the VAS for speculum insertion, tenaculum placement, during IUD insertion, post-IUD insertion, and prior to discharge, [8] provider ease, [9] race/ethnicity, and [10] parity. All reviewers worked independently to extract data from the included studies, followed by a final review of all study data by a single reviewer.\u003c/p\u003e\n\u003ch3\u003eOutcome definitions\u003c/h3\u003e\n\u003cp\u003ePain outcomes, as measured by a VAS scoring system at the time of IUD insertion, were defined as our primary outcome. Pain outcomes at the time of speculum insertion, tenaculum placement, post-IUD insertion, prior to discharge, and provider-perceived ease of placement were defined as secondary outcomes.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eWe utilized the JADAD scoring guidelines to determine risk of bias assessment \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Two reviewers separately assessed all studies in our review and scored each based on the following criteria: the study was [1] randomized, [2] double blinded, and [3] accounted for withdrawals and dropouts. Additional points were given to those studies that described the method of randomization as well as the method of blinding. Points were withdrawn from those studies that used inappropriate methods of randomization or blinding.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eA network meta-analysis was conducted to compare the pharmacological interventions across studies. A random-effect model was assumed when pooling the study outcomes. Before pooling, all VAS scores were converted to a scale of 0-100. When mean or standard deviation (SD) were not reported, they were approximated by median and interquartile range (IQR) using Method 4 in Greco et al 2015, or range using the formula in Hozo et al 2005\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The results of the network meta-analysis were presented in [1] network geometry, [2] a forest plot, and [3] a league table. Network geometry showed the structure of evidence, where each treatment was represented by a node, the thickness of a linkage between every two nodes indicated the number of studies directly comparing the two treatments, and the size of a node indicated the combined sample size for each treatment. The forest plot included a \u003cem\u003eP\u003c/em\u003e-score on a scale of zero to one for each treatment that can be interpreted as the likelihood of that treatment being the best option. While \u003cem\u003eP\u003c/em\u003e-scores provided a relative ranking of the treatments, they did not necessarily infer a significant difference between any two treatments. To further examine the significance of the difference, we referred to the mean differences (MD) and 95% confidence intervals (CI) in the forest plot for the comparison between each treatment and placebo, and the league table for the comparison between one pharmacological treatment to another pharmacological treatment. A 95% CI that did not cross zero indicated a significant difference. Heterogeneity among studies was assessed by the I\u0026sup2; statistic and Cochran\u0026rsquo;s Q test. Consistency between direct and indirect evidence was not assessed since in all included studies, the pharmacological treatments were compared to placebo or no treatment.\u003c/p\u003e \u003cp\u003eIn the presence of heterogeneity, random-effect univariate meta-regression was conducted to explore the potential source of heterogeneity among studies, e.g. mean age, ratio of nulliparous participants, ratio of Caucasian participants, ratio of African American participants, ratio of Hispanic participants, route of delivery, JADAD score, and VAS range. We included this in our paper to highlight potential disparities in pain perception and overall pain experiences to ensure a more comprehensive approach to reproductive healthcare.\u003c/p\u003e \u003cp\u003eFinally, the presence of publication bias was assessed by the funnel plot and Egger test. Meta-regressions, funnel plots, and Egger tests were only performed for outcomes with 10 or more studies. All statistical analyses were performed in R v.4.1.2 and package \u003cem\u003enetmeta\u003c/em\u003e and \u003cem\u003emeta\u003c/em\u003e were used for the network meta-analysis and meta-regression, respectively. \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eLiterature Search\u003c/h2\u003e\n \u003cp\u003eThe literature search identified a total of 397 citations. After the PRISMA selection process, 16 trials remained for data extraction. The flow diagram in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e describes the selection process. Study characteristics and demographic data are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDescriptive characteristics of United States Clinical Trials evaluating pain with IUD insertion from 2011\u0026ndash;2024\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor, Year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy Type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJadad Score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubstance\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDosage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRoute of Delivery\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParticipant # in Trial\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParticipant # in TG\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParticipant # in PG\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean age (TG)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean age (PG)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEligibility\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParity (TG)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParity (PG)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBerens, 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1%, Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParacervical\u003c/p\u003e\n \u003cp\u003eblock\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo analgesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;52 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 NP\u003c/p\u003e\n \u003cp\u003e22 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicks, 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNO Donor - Nitroglycerin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo Ointment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLathrop, 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMisoprostol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mcg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrally (buccally)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentical pill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBednarek, 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNO Donor - Nitroprusside\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 mg, 1 mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo gel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAllen, 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2%, 120 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInert gel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;49 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 NP\u003c/p\u003e\n \u003cp\u003e69 MP (11 C, 58 V)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 NP\u003c/p\u003e\n \u003cp\u003e68 MP (17 C, 51 V)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSwenson, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMisoprostol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mcg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally or Buccally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIdentical pill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18 y/o or older\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConti, 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2%, 10 mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgical Lubricant Jelly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMD\u0026thinsp;=\u0026thinsp;28.9 range (18\u0026ndash;48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMD\u0026thinsp;=\u0026thinsp;27.0 range (18\u0026ndash;51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18 y/o or older\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 NP\u003c/p\u003e\n \u003cp\u003e11 C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 NP\u003c/p\u003e\n \u003cp\u003e6 C\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMody, 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1%, 18 mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParacervical block\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSham block\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaguire, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2%, 1 mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgilube gel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 NP\u003c/p\u003e\n \u003cp\u003e61 P (18 C, 43 V)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 NP\u003c/p\u003e\n \u003cp\u003e79 P (16 C, 63 V)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMody, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1%, 10 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParacervical block\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;50 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 NP\u003c/p\u003e\n \u003cp\u003e17 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 NP\u003c/p\u003e\n \u003cp\u003e16 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNgo, 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNSAID - Toradol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 mg in 1 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntramuscular injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;50 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 NP\u003c/p\u003e\n \u003cp\u003e25 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 NP\u003c/p\u003e\n \u003cp\u003e26 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMcNicholas, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2%, 3\u0026ndash;5 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWater based lubricant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 NP\u003c/p\u003e\n \u003cp\u003e50 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 NP\u003c/p\u003e\n \u003cp\u003e49 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNgo, 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNSAID - Naproxen Sodium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e550 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo tablet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18 y/o or older\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 NP\u003c/p\u003e\n \u003cp\u003e1 P\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 NP\u003c/p\u003e\n \u003cp\u003e2 P\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEdelman, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMisoprostol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mcg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrally (Buccally)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo pill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;45 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 NP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChor, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNSAID - Ibuprofen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e800 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo pill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.66\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.89\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18 y/o or older\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 NP\u003c/p\u003e\n \u003cp\u003e41 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 NP\u003c/p\u003e\n \u003cp\u003e37 MP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNelson, 2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTB-RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLidocaine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2%, 1.3 cc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometrial Infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.05 range (20\u0026ndash;43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.06 range (19\u0026ndash;46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF 18\u0026ndash;50 y/o\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003ctable id=\"Taba\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Female, \u003cstrong\u003eNP\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Nulliparous, \u003cstrong\u003eMP\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Multiparous, \u003cstrong\u003eP\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Parous, \u003cstrong\u003eC\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Cesarean, \u003cstrong\u003eV\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Vaginal, \u003cstrong\u003eTG\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Treatment Group, \u003cstrong\u003ePG\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Placebo Group, \u003cstrong\u003eRCT\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Randomized Controlled Trials, \u003cstrong\u003eQB\u0026thinsp;=\u003c/strong\u003e\u0026thinsp;Quadruple blinding, \u003cstrong\u003eTB\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Triple Blinded\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDB\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Double Blinded, \u003cstrong\u003eMD\u003c/strong\u003e\u0026thinsp;=\u0026thinsp;Median\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eCharacteristics of studies\u003c/h2\u003e\n \u003cp\u003eOf the included studies, eight assessed the use of lidocaine during IUD insertion. Four of these studies applied lidocaine gel vaginally to the cervix while the placebo arm used a placebo gel, in both nulliparous and multiparous participants \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Three studies performed paracervical blocks with lidocaine; two were against no treatment in both nulliparous and multiparous participants and one was against a sham paracervical block in nulliparous individuals only \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. The remaining study assessed the use of lidocaine endometrial infusion during IUD insertion versus normal saline endometrial infusion \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThe use of NSAIDs (Toradol, Naproxen Sodium \u0026amp; Ibuprofen) during IUD insertion was assessed in three studies. Two of which used an oral route of delivery while the other performed through intramuscular (IM) injection against placebo tablets and saline injection, respectively, in both nulliparous and multiparous individuals \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eMisoprostol was studied in three clinical trials and administered buccally in nulliparous individuals only. However, one trial gave patients the choice between buccal or vaginal administration. All trials utilized an identical tablet in the placebo arm \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eNitric oxide (NO) donors were studied in two clinical trials, specifically nitroglycerin and nitroprusside. Both NO donors were in the form of a gel and administered vaginally to the cervix in nulliparous individuals only \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eMost of the studies included assessing patient-reported pain during IUD insertion using the VAS, with scores ranging from 0-100. There were four studies that utilized the VAS with a range of 0\u0026ndash;10; one from the NSAID group and three from the lidocaine group, while the lidocaine endometrial infusion trial utilized a VAS with a range of 0\u0026ndash;9\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eAdditionally, the mean and SD of the VAS were reported in most of the studies. There were six studies that reported median, two of which were accompanied by IQR (one from the IM NSAID group and one from the oral NSAID group), and three with range only (two from the vaginal lidocaine group and one from the oral misoprostol group) \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. It is to be noted that McNicholas 2012 reported median and range only while utilizing the VAS with a range of 0\u0026ndash;10\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. The mean and SD were converted and approximated before pooling, therefore, interpretation of the results involving this study should be made with caution.\u003c/p\u003e\n \u003cp\u003eThe quality of randomization and blinding of the discussed clinical trials were assessed by the JADAD scoring guidelines and documented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. 14 of the 16 studies scored a maximum of five out of five points, indicating the studies are of high quality. The other two studies scored a two out of five as there was no placebo arm, the method of randomization was not specified, and both patients and investigators were unblinded \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary outcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\n \u003ch2\u003eIUD insertion\u003c/h2\u003e\n \u003cp\u003e16 studies with 1,488 biological women were included in the IUD insertion network. As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, P-scores associated with each substance studied during IUD insertion were generated with paracervical lidocaine having the largest likelihood of being the best treatment option (\u003cem\u003eP\u003c/em\u003e-score\u0026thinsp;=\u0026thinsp;0.85) and oral misoprostol having the smallest likelihood of being the best treatment option (\u003cem\u003eP\u003c/em\u003e-score\u0026thinsp;=\u0026thinsp;0.08). Paracervical lidocaine was associated with significantly greater pain reduction than placebo (MD: -14.6; 95% CI: -27.5, -1.7) and oral misoprostol (MD: -25.8; 95% CI: -43.8, -7.7). The differences between other treatment options were not significant. The heterogeneity among studies was significant (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;70%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eBased on the univariate meta-regression (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), the VAS pain scale (71.9%), route of delivery (43.6%), ratio of African American women (20.7%), JADAD scores (15.8%), and ratio of nulliparous women (15.5%) were likely to be responsible for the heterogeneity, comparing to mean age, ratio of Caucasian women, and ratio of Hispanic women (all 0%). Studies using 0-100 VAS pain scale reported significantly less pain reduction than studies using 0\u0026ndash;10 (or 0\u0026ndash;9) VAS pain scale (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). Studies using other routes of delivery (IM, intrauterine, paracervical) reported greater pain reduction than studies using orally route of delivery, regardless of the substance used (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\n \u003cp\u003eAlthough statistically insignificant (\u003cem\u003eP\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/em\u003e), studies with higher ratios of nulliparous women may be reporting less pain reduction, and studies with higher ratios of African American women may be reporting greater pain reduction. It is to be noted in the bubble plot (Figure s1) that McNicholas 2012, a large study that reported median and range only using a 0\u0026ndash;10 VAS, apparently deviates away from the regression line between ratio of nulliparous women and mean VAS differences \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. This study, together with the small number of studies available for meta-regression, may be causing the relationship to appear insignificant. However, the trend should not be ignored, and further investigation is warranted. For the evaluation of publication bias, while there may be some visible asymmetry in the funnel plot (Figure s2), Egger\u0026rsquo;s test did not reach statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.23). For the sensitivity analysis, we excluded McNicholas 2012 from the IUD insertion network and found paracervical lidocaine to still have the largest likelihood of being the best treatment option while oral misoprostol had the smallest likelihood.\u003c/p\u003e\n \u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate Meta-Regression: assessment of covariates associated with pain reduction during IUD Insertion\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eCovariate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eIUD Insertion\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRegression Coefficient\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHeterogeneity Explained\u003c/p\u003e\n \u003cp\u003eBy Covariate (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.9 (-2.8 to 1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRatio of Caucasian Women\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.6 (-9.1 to 22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRatio of African American Women\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-18.0 (-49.0 to 13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRatio of Hispanic Women\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9 (-25.9 to 31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRatio of Nulliparous Women\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.4 (-3.8 to 18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRoute of Delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.004*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVaginally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-8.5 (-17.3 to 0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther (Intramuscular,\u003c/p\u003e\n \u003cp\u003eIntrauterine, Paracervical)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-20.6 (-32.7 to -8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eJADAD Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.0 (-0.9 to 8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eVAS Pain Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0-100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ereference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u0026ndash;10 (or 0\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-9.6 (-16.6 to -2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eThe results of the network meta-analysis for the secondary outcomes can be found in Figure s3-s7. NSAIDs (IM) had the largest likelihood of being the best treatment option in reducing pain during speculum insertion, tenaculum placement, post-IUD insertion, and prior to discharge (\u003cem\u003eP\u003c/em\u003e-score\u0026thinsp;=\u0026thinsp;0.89, 0.80, 0.85, and 0.87, respectively). However, most of the differences were not significant, except for the pain prior to discharge. Greater pain reduction was perceived prior to discharge if NSAIDs (IM) were used as opposed to lidocaine (vaginally), placebo, or misoprostol (both routes). On the other hand, vaginal misoprostol had the largest likelihood of being the best option in increasing provider ease (\u003cem\u003eP\u003c/em\u003e-score\u0026thinsp;=\u0026thinsp;0.89), and was significantly better than placebo (MD: -2.3; 95% CI: -3.6, -1.0).\u003c/p\u003e\n \u003cp\u003eSignificant heterogeneity was only detected in the tenaculum placement network (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;60%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). The results of the univariate meta-regression for tenaculum placement can be found in Table s1 and Figure s8. No significant relationship was found, but mean age and ratio of Hispanic individuals account for 48.7% and 34.6% of the heterogeneity, respectively. Although insignificant, studies with participants of higher mean age may be reporting greater pain reduction during tenaculum placement, and studies with higher ratios of Hispanic individuals may be reporting less pain reduction. Since older individuals are more likely to be multiparous, this trend is consistent with the trend observed in IUD insertion. For the evaluation of publication bias, while there may be some visible asymmetry in the funnel plot (Figure s9), Egger\u0026rsquo;s test did not reach statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis review revealed that paracervical lidocaine was the most effective pharmacological pain management intervention with IUD insertion, shown through lower VAS pain scores. Specifically, paracervical lidocaine was shown to be a better intervention for pain management than oral misoprostol and placebo groups, consistent with findings in previous literature against placebos \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. This study systematically compares analgesics and their various routes of administration from United States clinical trials, including NSAIDs (administered orally and IM), lidocaine (administered intrauterine and vaginally), misoprostol (administered orally and vaginally), NO donors (administered vaginally), and placebo, further emphasizing the usefulness of this study in clinical practice.\u003c/p\u003e \u003cp\u003eOur data highlights that the IUD insertion process is a multifaceted and personalized procedure influenced by patient characteristics, provider preferences, and pain management options. The provider preference, typically determined by ease, can conflict with what may be better suited for pain management for the patient, further exacerbating individualized pain management. We identified that the preferential method for providers during IUD insertion was utilizing vaginal misoprostol over the placebo treatment. The rational for using misoprostol is that by both dilating and softening the cervix, it can facilitate an easier IUD insertion for the provider, which may result in a less painful experience for the patient \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere were no significant differences among pharmacological treatments for speculum insertion, tenaculum placement, and post IUD insertion noted in our data analysis. However, our findings indicated several significant differences between pharmacological pain management options for pain prior to discharge, with NSAIDS (IM) yielding the greatest pain reduction perceived prior to discharge.\u003c/p\u003e \u003cp\u003eFurthermore, this study reinforces the various patient characteristics that influence pain, ranging from age and ethnic background to parity. Previous studies have reported greater pain in people older than 30 years of age, nulliparous individuals, and patients with a history of dysmenorrhea \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. In our meta-analysis, the ratio of nulliparous and African American individuals explained 20.7% and 15.5% of the heterogeneity seen in the resultant pain reduction during IUD insertion respectively, which suggests their influence on pain consistently across studies.\u003c/p\u003e \u003cp\u003eWith the analysis of data from 16 clinical trials, we have provided an updated network meta-analysis on pharmacological pain management for IUD insertion. This contributes to a growing body of data and provides a foundation for future research by identifying gaps in existing literature that can be further examined.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eA challenging limitation to address, yet appreciated as a factor in pain perception, is the subjectivity and complexity of pain. Nulliparity, ethnicities, past medical history, including histories of sexually transmitted infections (STIs) and pelvic inflammatory disease (PID), and type of IUD all play a role in pain. As a result of this limited information, we were unable to stratify these confounders when evaluating pain. There may even be other confounders that are not appreciated in the perception of pain that need to be further investigated, such as the patient's anxiety and experience with having an IUD placed, a negative perception of IUDs, ovulation cycle timing, and age at IUD placement. In fact, a recent study in 2019 showed that the negative perception of IUDs was the strongest predictor of pain with IUD insertion in parous women\u003csup\u003e[34]\u003c/sup\u003e. Thus, the subjective nature of pain limits our ability to sufficiently generalize pain reduction.\u003c/p\u003e \u003cp\u003eOur inclusion criteria was an additional limiting factor to our study. We solely used the VAS to quantify pain, thus simplifying a qualitative experience for the sake of data extraction and interpretation. The inclusion of biological women at or above the age of 18 years old also reduced the ability to generalize our results. The rationale for excluding individuals under the age of 18 years old was intended to minimize variables that impact pain scores that may be reported by adolescents. In the United States, adolescents do not typically undergo routine pelvic examinations until the age of 21 years old, thus, the insertion of an IUD may be their first experience with a gynecologic procedure which may increase both the anticipation of pain and pain during the procedure \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBy conducting a network meta-analysis, the results of this study can apply to a more diverse patient population. However, due to the small number of studies available, the meta-regression was underpowered in detecting significant effect modifiers. External validity is also constrained by the limited number of participants in the clinical trials, and our exclusive utilization of trials conducted in the United States. International data may provide a different perspective on the influences that determine pain.\u003c/p\u003e \u003cp\u003eWe recognize that this comparison relies on the availability of relevant information based on published current trials. Since our study relied on clinical trials that had accessible results, we were subjected to the pharmacological agents used in the trials as the basis of our meta-analysis. Thus, there could be many other pharmacological agents utilized in clinical trials that were not evaluated due to results not being posted at the time of discovery or because the trials were not listed on the registry that may provide additional pain reduction.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eFuture research\u003c/h2\u003e \u003cp\u003eIn general, our study found that multiparous women and older women may experience greater pain reduction, and that the treatments seemed less effective for both nulliparous and younger women. Additionally, nulliparous women reported greater pain in comparison to multiparous women with IUD placement, likely due to the absence of cervical dilation that results after childbirth in multiparous women \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. This suggests an implication to increase medication dosages in both nulliparous and younger women, prompting an investigation of this potential benefit in future studies.\u003c/p\u003e \u003cp\u003eEthnic minorities such as African American and Hispanic patients have historically been undertreated for pain due to systemic inequalities, leading them to report greater pain and contributing to health disparities amongst these racial groups \u003csup\u003e[\u003cspan additionalcitationids=\"CR39\" citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. Because our analysis identified ethnicity as a potential influencing factor in pain, future research should explore this role; a new, holistic approach to pain management that has yet to be appreciated. Such research will enable the development of culturally competent interventions and improve pain mitigation strategies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe purpose of this meta-analysis was to evaluate the pharmacologic pain management options during IUD insertion and to provide an update on the current literature. Our findings suggest that paracervical lidocaine may be the most effective pharmacological intervention for pain management during an IUD insertion, as indicated by comparatively lower VAS pain scores. Accordingly, it is reasonable to suggest that providers consider the use of paracervical lidocaine as a potential pain management option for IUD insertion. In contrast, oral misoprostol was the least effective in lowering patient VAS pain scores during IUD insertion. Future studies should be directed towards larger sample sizes and facilitation towards robust multivariate meta-regression analyses to understand and stratify the role of the variables that affect pain.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participant\u003c/strong\u003e:\u0026nbsp;Formal ethical approval was not required as this study was a systematic review and network meta-analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All data generated or analyzed during this study are included in this published article and supplementary materials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e There has been no financial incentive for conducting this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e JT registered the study. JT and KB were primary contributors in the writing of the manuscript as well as the literature search. BP and JT contributed to the introduction. JT and DB contributed to the study design. MW and AW conducted the statistical analysis and data extraction, including the random-effect univariate meta-regression and assessment of publication bias through the funnel plot and Egger tests; MW and AW reported on these outcomes through primary and secondary outcomes. AH and BP created the figure1 and table 1 based on our data and contributed to the discussion with KB. DB provided oversight for the systematic approach and ensured adherence to PRISMA guidelines. RH provided oversight on the clinical significance of our findings and provided a medical background on IUD use. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Not applicable\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCenters for Disease Control and Prevention. \u0026ldquo;Contraception.\u0026rdquo; Reproductive Health. Published 28 May 2024, www.cdc.gov/reproductive-health/contraception/?CDC_AAref_Val=www.cdc.gov/reproductivehealth/contraception/index.htm. Accessed 29 Apr., 2024.\u003c/li\u003e\n \u003cli\u003ePeipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. \u003cem\u003eObstet Gynecol\u003c/em\u003e. 2011;117(5):1105-1113. doi:10.1097/AOG.0b013e31821188ad. Accessed 24 May, 2024.\u003c/li\u003e\n \u003cli\u003eHubacher D, Grimes DA. 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Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eBerens P. Paracervical block versus no paracervical block during IUD insertion. \u003cem\u003eClinicalTrials.gov\u003c/em\u003e. Identifier: NCT02904915. Available at: https://clinicaltrials.gov/ct2/show/NCT02904915. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eMody SK, Kiley J, Rademaker A, Gawron L, Stika C, Hammond C. Pain control for intrauterine device insertion: a randomized trial of 1% lidocaine paracervical block. \u003cem\u003eContraception\u003c/em\u003e. 2012;86(6):704-709. doi:10.1016/j.contraception.2012.06.004. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eNelson AL, Fong JK. Intrauterine infusion of lidocaine does not reduce pain scores during IUD insertion. \u003cem\u003eContraception\u003c/em\u003e. 2013;88(1):37-40. doi:10.1016/j.contraception.2012.12.009. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eNgo LL, Ward KK, Mody SK. Ketorolac for Pain Control With Intrauterine Device Placement: A Randomized Controlled Trial. \u003cem\u003eObstet Gynecol\u003c/em\u003e. 2015;126(1):29-36. doi:10.1097/AOG.0000000000000912. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eNgo LL, Braaten KP, Eichen E, Fortin J, Maurer R, Goldberg AB. Naproxen Sodium for Pain Control With Intrauterine Device Insertion: A Randomized Controlled Trial. \u003cem\u003eObstet Gynecol\u003c/em\u003e. 2016;128(6):1306-1313. doi:10.1097/AOG.0000000000001746. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eChor J, Bregand-White J, Golobof A, Harwood B, Cowett A. Ibuprofen prophylaxis for levonorgestrel-releasing intrauterine system insertion: a randomized controlled trial. \u003cem\u003eContraception\u003c/em\u003e. 2012;85(6):558-562. doi:10.1016/j.contraception.2011.10.015. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eLathrop E, Haddad L, McWhorter CP, Goedken P. Self-administration of misoprostol prior to intrauterine device insertion among nulliparous women: a randomized controlled trial. \u003cem\u003eContraception\u003c/em\u003e. 2013;88(6):725-729. doi:10.1016/j.contraception.2013.07.011. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eSwenson C, Turok DK, Ward K, Jacobson JC, Dermish A. Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. \u003cem\u003eObstet Gynecol\u003c/em\u003e. 2012;120(2 Pt 1):341-347. doi:10.1097/AOG.0b013e31825d9ec9. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eEdelman AB, Schaefer E, Olson A, et al. Effects of prophylactic misoprostol administration prior to intrauterine device insertion in nulliparous women. \u003cem\u003eContraception\u003c/em\u003e. 2011;84(3):234-239. doi:10.1016/j.contraception.2011.01.016. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eMicks EA, Jensen JT, Bednarek PH. The effect of nitroglycerin on the IUD insertion experience in nulliparous women: a pilot study. \u003cem\u003eContraception\u003c/em\u003e. 2014;90(1):60-65. doi:10.1016/j.contraception.2014.03.012. Accessed 7 Feb., 2024.\u003c/li\u003e\n \u003cli\u003eZapata LB, Nguyen A, Snyder E, et al. Misoprostol for intrauterine device placement. \u003cem\u003eCochrane Database Syst Rev\u003c/em\u003e. 2022;2022(7):CD015584. Published 2022 Jul 21. doi:10.1002/14651858.CD015584.\u003c/li\u003e\n \u003cli\u003eHubacher D, Reyes V, Lillo S, Zepeda A, Chen PL, Croxatto H. Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e. 2006;195(5):1272-1277. doi:10.1016/j.ajog.2006.08.022. Accessed 1 Apr., 2024.\u003c/li\u003e\n \u003cli\u003e\u003csup\u003e\u0026zwnj;\u003c/sup\u003eAkdemir Y, Karadeniz M. The relationship between pain at IUD insertion and negative perceptions, anxiety and previous mode of delivery. \u003cem\u003eThe European Journal of Contraception \u0026amp; Reproductive Health Care\u003c/em\u003e. 2019;24(3):240-245. doi:https://doi.org/10.1080/13625187.2019.1610872. Accessed 1 Apr., 2024.\u003c/li\u003e\n \u003cli\u003eBrima N, Akintomide H, Iguyovwe V, Mann S. A comparison of the expected and actual pain experienced by women during insertion of an intrauterine contraceptive device. \u003cem\u003eOpen Access J Contracept\u003c/em\u003e. 2015;6:21-26. Published 2015 Feb 16. doi:10.2147/OAJC.S74624.\u003c/li\u003e\n \u003cli\u003eMutch DG. Why annual pap smears are history \u0026ndash; but routine OB-GYN visits are not. ACOG. Accessed May 3, 2025. https://www.acog.org/womens-health/experts-and-stories/the-latest/why-annual-pap-smears-are-history-but-routine-ob-gyn-visits-are-not. \u003c/li\u003e\n \u003cli\u003eChi IC, Galich LF, Tauber PF, et al. Severe pain at interval IUD insertion: a case-control analysis of patient risk factors. \u003cem\u003eContraception\u003c/em\u003e. 1986;34(5):483-495. doi:10.1016/0010-7824(86)90057-0. Accessed 1 Apr., 2024.\u003c/li\u003e\n \u003cli\u003eHoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e. 2016;113(16):4296-4301. doi:10.1073/pnas.1516047113. Accessed 1 May, 2024.\u003c/li\u003e\n \u003cli\u003eMossey JM. Defining racial and ethnic disparities in pain management. \u003cem\u003eClin Orthop Relat Res\u003c/em\u003e. 2011;469(7):1859-1870. doi:10.1007/s11999-011-1770-9. Accessed 1 Apr., 2024.\u003c/li\u003e\n \u003cli\u003eReyes-Gibby CC, Aday LA, Todd KH, Cleeland CS, Anderson KO. Pain in aging community-dwelling adults in the United States: non-Hispanic whites, non-Hispanic blacks, and Hispanics. \u003cem\u003eJ Pain\u003c/em\u003e. 2007;8(1):75-84. doi:10.1016/j.jpain.2006.06.002. Accessed 1 Apr., 2024.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"A.T. Still University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Analgesia, Intrauterine device, Pain, Pharmacological intervention, Paracervical lidocaine","lastPublishedDoi":"10.21203/rs.3.rs-6590141/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6590141/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo identify the most effective pain management intervention during intrauterine device (IUD) insertion based on recent clinical trials in the United States.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAn electronic search was conducted in the following databases and registry for studies conducted in the United States: Medline via PubMed, SCOPUS, and Clinicaltrials.gov. Data collection occurred between February 7th, 2024, to March 3rd, 2024. Examination of 16 studies, involving 1,524 individuals was utilized in this meta-analysis. Selection criteria included Randomized Controlled Trials (RCT) conducted in the United States, biological women receiving IUDs at the age of 18 years or older, trials comparing treatments to placebo or no treatment, and trials that used the Visual Analogue Scale (VAS) for pain scores. A standard Google Sheets spreadsheet was used to perform data entry. The present review was designed according to the PRISMA guidelines for reporting of systematic reviews incorporating network meta-analyses of health care interventions and was submitted to PROSPERO accordingly (identifier: CRD42024534207).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e We utilized the JADAD scoring guidelines to determine risk of bias assessment through two different reviewers. Network meta-analysis using a random effect model was performed to compare the various pharmacological interventions. The results of the comparison were presented in forest plots and league tables using P-scores and mean differences with 95% confidence intervals. Heterogeneity among studies was assessed by the I\u0026sup2; statistic and Cochran\u0026rsquo;s Q test, and random-effect univariate meta-regression was conducted to explore the source of heterogeneity. Among the four different substances studied, only paracervical lidocaine was significant in producing lower VAS pain scores related to intrauterine device insertion as opposed to placebo (mean difference: -14.6; 95% confidence interval: -27.5, -1.7) and as opposed to oral misoprostol (mean difference: -25.8; 95% confidence interval: -43.8, -7.7).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eParacervical lidocaine showed the greatest reduction in VAS pain scores during IUD insertion, thus supporting that paracervical lidocaine may be used as a pain management option for future intrauterine device implantation. Future studies should focus on clinical trials utilizing a consistent VAS pain scale and targeting specific subpopulations.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003e This review has been registered on May 2024 through Prospero with the identifier number: CRD42024534207.\u003c/p\u003e","manuscriptTitle":"Effective Pharmacologic Pain Management Interventions for Intrauterine Device Insertion: A Systematic Review and Network Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 08:27:22","doi":"10.21203/rs.3.rs-6590141/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"57f7074b-a590-4d4b-84b5-3785b97ac3c4","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48120351,"name":"Obstetrics \u0026 Gynecology"},{"id":48120352,"name":"Sexual \u0026 Reproductive Medicine"}],"tags":[],"updatedAt":"2025-05-06T08:27:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-06 08:27:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6590141","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6590141","identity":"rs-6590141","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}