Interventions for the prevention of pain associated with the placement of intrauterine contraceptives: An updated review

Abstract A 2013 review found no evidence to support the routine use of pain relief for intrauterine contraceptive (IUC) placement; however, fear of pain with placement continues to be a barrier to use for some women. This narrative review set out to identify (1) new evidence that may support routine use of pain management strategies for IUC placement; (2) procedure‐related approaches that may have a positive impact on the pain experience; and (3) factors that may help healthcare professionals identify women at increased risk of pain with IUC placement. A literature search of the PubMed and Cochrane library databases revealed 550 citations, from which we identified 43 new and pertinent studies for review. Thirteen randomized clinical trials, published since 2012, described reductions in placement‐related pain with administration of oral and local analgesia (oral ketorolac, local analgesia with different lidocaine formulations) and cervical priming when compared with placebo or controls. Four studies suggested that ultrasound guidance, balloon dilation, and a modified placement device may help to minimize the pain experienced with IUC placement. Eight publications suggested that previous cesarean delivery, timing of insertion relative to menstruation, dysmenorrhea, expected pain, baseline anxiety, and size of insertion tube may affect the pain experienced with IUC placement. Oral and local analgesia and cervical priming can be effective in minimizing IUC placement‐related pain when compared with placebo, but routine use remains subject for debate. Predictive factors may help healthcare professionals to identify women at risk of experiencing pain. Targeted use of effective strategies in these women may be a useful approach while research continues in this area.


| INTRODUC TI ON
Intrauterine contraceptives (IUC) are highly effective and safe methods of pregnancy prevention. 1 Greater awareness and use could help to reduce the incidence of unplanned or mistimed pregnancy. 2,3 The US-based Contraceptive CHOICE Project reported that provision of accurate, unbiased counseling on long-acting reversible contraceptive methods, and removal of cost barriers, led to the majority of the women choosing IUC. 2 A subsequent review of the impact of the CHOICE project showed that use of long-acting reversible contraceptive methods led to higher rates of continued contraceptive use and a reduction in the average annual rates of pregnancy, birth and abortion among teenage participants. 3 For most women, pain experienced with IUC placement is mild to moderate and less than anticipated. 4,5 However, some women remain anxious about the possibility of pain or are more likely to be affected by factors such as nulliparity, or a long time period since delivery. In addition, anatomical, cultural or psychological elements can contribute to a more painful experience. 6,7 Fear of pain at the time of placement can therefore be a barrier to choosing IUC. 6,8,9 In a survey of pain and discomfort, both at the time of IUC placement and as a recollection, experienced by parous and nulliparous women participating in a UK-based contraceptive service, Murty 9 found that women anticipating pain were more anxious and more likely to take analgesia before placement. Although their pain scores during the procedure were similar to those of women who had not taken analgesia, their recollection of the pain experienced when asked 6 months later was greater than they reported immediately post-placement.
Healthcare professional concerns about difficult and/or painful placement may also discourage discussion of IUC as a contraceptive option and lead to the counseling of women on other, less effective methods. 10 A literature review to evaluate the evidence for strategies to minimize pain experienced during IUC placement, carried out in 2012, led to a consensus that no prophylactic pharmacological intervention had been adequately studied to support its routine use. 11 Furthermore, in a Cochrane Review of interventions to minimize pain associated with IUC placement, the authors concluded that some oral analgesics and lidocaine formulations are effective in reducing placement-related pain in specific groups but that most of the evidence came from single trials and were of moderate quality. 8 We undertook an updated review to determine whether there was any new evidence for pharmacological interventions to minimize pain associated with IUC placement, to identify whether nonpharmacological or procedure-related interventions could prove helpful. We also set out to identify any factors that may assist in predicting the women most likely to experience pain.

| MATERIAL AND ME THODS
The broader objectives of this review, together with the diversity of populations and interventions and lack of consistent and validated assessment of pain experience, limits the possibility of a systematic review or meta-analysis. 12 Consequently, we opted to undertake a narrative review, an approach that is based on systematic methodologies, employs a bibliographic research strategy, 13,14 and looks at the evidence contributing to the clinical concept of pain relief during IUC placement.
We searched the PubMed and Cochrane databases to update and extend the findings of our original review. 11 We conducted a search for publications in any language that reported pharmacological interventions to reduce pain with IUC placement using the terms "intrauterine contraception" AND "insertion" AND "pain" published from December 2012 to September 2018. We then conducted a search of publications from January 1980 to September 2018, the timeframe of the original and our updated review combined, to identify other approaches that may influence pain experience or predict the experience of pain. We used a combination of text and MeSH terms: "intrauterine contraception" OR "levonorgestrel-releasing intrauterine system" OR "LNG-IUS" OR "IUD" AND "pain" OR "anxiety" OR "fear" OR "counseling" OR "insertion" OR "placement" OR "initiation" OR "cervical priming" OR "cervical ripening." The search was not limited to randomized controlled trials and results were cross-referenced and duplicate publications were removed.
The search identified 550 publications ( Figure 1). Those not relevant to pain management either before or after IUC placement; those included in the previously published review 11 ; and those reporting the findings of reviews were excluded. The final number of publications included in our review was 43. We assessed these publications for information relating to the effect of pharmacological interventions (pre-insertion oral or local analgesia, cervical priming, post-insertion analgesia), nonpharmacological strategies or procedure-related factors on the pain experienced with IUC placement. We also assessed publications for factors that may help to predict the likelihood of experiencing pain with placement.
Assessment of risk of bias of R randomized clinical trials (RCTs) included in the review was carried out according to the Cochrane Collaboration Handbook for Systematic Reviews of Interventions. 15 As the intention was to conduct a narrative review rather than a systematic review the assessment of bias was limited to RCTs. No non-English publications were identified for inclusion.
between the intervention and placebo/control groups, and level of evidence from each study reporting pain-relieving interventions is summarized in Table 1. The clinical relevance and statistical significance of differences in pain scores between the intervention and placebo/control groups are also noted. There is a degree of overlap across the study descriptions as some studies described multiple interventions relevant to more than one category.

| Characteristics and methods of included studies
Among the reviewed publications, 26 described pre-placement pharmacological interventions to minimize pain associated with IUC placement.  Of these, 25 were RCTs  and one was a nonrandomized comparator study. 41 Eight publications-of which six described RCTs, [42][43][44][46][47][48] one was a pilot feasibility study 45 and one was a pooled analysis 49 described nonpharmacological interventions. A further nine publications described factors related to the experience of pain with IUC placement. [50][51][52][53][54][55][56][57][58] Of these, one was an RCT, 50 three were non-RCTs, 51-53 three were prospective cohort studies, [54][55][56] one was a case-control study, 57 and one was a secondary analysis of the US-based Contraceptive CHOICE Project. 58 All studies evaluating pharmacological interventions except for Nelson and Fong 40 reported the use of a 10-cm or 100-mm visual analogue scale (VAS), where 0 is equivalent to "no pain" and 10 is equivalent to "worst pain ever", by study participants to indicate the severity of pain experienced. Nevertheless, there were wide variations in the assessment of the experience of pain in terms of timing (IUC placement only); IUC placement plus other time-points (speculum insertion, tenaculum placement, uterine sounding); postplacement assessment (multiple time intervals); overall perception of pain.

| Pre-insertion pharmacological therapy: Oral analgesia
Five RCTs evaluated the effectiveness of oral analgesia on the experience of pain with IUC placement [16][17][18][19][20] and one RCT compared multiple analgesic agents. 21 One RCT, reported a 15-mm reduction in mean pain score with oral ketorolac (20 mg) given 40-60 minutes before IUC placement when compared with placebo. 16 Although statistically significant, the authors suggested that the time required for the maximum analgesic effect of ketorolac (1-2 hours after administration) may have affected the F I G U R E 1 Literature selection process for review Pre-insertion oral analgesia N = 5 (5 RCTs) Pre-insertion cervical priming N = 5 (5 RCTs) Pre-insertion local analgesia N = 16 (  and ibuprofen compared with placebo, 19,20 found no difference in mean pain scores at the time of IUC placement between the treatment and control groups; however, a reduction in median pain score was observed at 5 minutes (9 mm) and 15 minutes (11.2 mm) after IUC placement in the naproxen sodium group when compared with placebo. 17

| Pre-insertion pharmacological therapy: Cervical priming
Three RCTs found pain scores with IUC placement to be lower following vaginal administration of misoprostol when compared with placebo (Table 2)

| Lidocaine-prilocaine cream
Two studies 31,32 reported 1.9-3.5 cm reductions on a 10-cm VAS in mean pain scores at multiple time-points during placement in parous women following application of LP cream when compared with the control group. In the study by Karasu et al, 31 use of LP cream did not lead to lower pain scores at either tenaculum or IUC placement when compared with controls (no anesthesia).

| Lidocaine gel
Authors of two studies 29

| Other local anesthesia approaches
Two RCTs, one comparing the effect of infusion of 1.2 mL of 2% lidocaine solution, administered by endometrial aspirator with placebo 40 and one comparing the effect of 0.5 mg nitroglycerin gel (1 mL) with placebo, 38 found no differences in mean pain scores between the treatment and control groups.

| Post-insertion pharmacological therapy
No new or additional studies were found in the updated literature search.

| Non-pharmacological pain management
The

| Predictors of the pain experience
Eight publications described factors that may help to predict women more likely to experience pain with IUC placement. [50][51][52][53][54][55][56][57][58] The identified factors are summarized in Table 2 A prospective cohort study 56 found that the mean post-placement pain experienced by nulliparous adolescents was higher than that among parous adult women on each day of the 2-week study (P < 0.05) and the greatest mean difference occurred in the first 4 days. The authors suggested that pain scores may have been affected by the detailed pre-and post-placement counseling of adolescent women provided by a trained Pediatric and Adolescent Gynecologist, which is uncommon in many settings and, therefore, different when compared with routine practice. 56 There was also a recommendation to use ibuprofen by one professional responsible for this arm of the study and eight adolescents had the placement procedure under sedation. 56 A secondary analysis of 1149 participants in the US Contraceptive CHOICE Project looked at whether anticipated pain affected actual pain experienced during IUC placement. 58 After controlling for parity, history of dysmenorrhea and type of IUC, higher anticipated pain was associated with an increase in experienced pain (adjusted risk ratio for 1 unit increase in anticipated pain, 1.19; 95% CI 1.14-1.25). 58 Nulliparity, history of dysmenorrhea, and placement of an LNG-IUS (with a 4.8-mm inserter) were all associated with an increase in mean pain score with IUC placement. As CHOICE was a prospective cohort study, real-time collection of anticipated and actual pain data limits recall bias and strengthens the study. 58 However, lack of information regarding the use of pain-relieving interventions, other than the routine offering of premedication with NSAIDs, may be a limiting factor.

| Assessment of risk of bias and quality of included studies
Each RCT included in the review was assessed for selection, performance, detection, attrition, and reporting bias by three authors (two assessors and one moderator) and the results are shown in Figure 2.
The majority of the remaining non-RCTs identified during our review described factors that may help identify those women at increased risk of pain with IUC placement. We did not assess these publications for risk of bias as their purpose was to provide insights into the potential for greater experience of pain than healthcare professionals may consider when counseling women regarding IUC. Given the nature of the review, ie narrative rather than systematic, assessment of quality of the RCTs did not extend beyond categorization according to the guidance of the Oxford Center for Evidence-Based Medicine. 60 Although 12 RCTs were identified as being at low risk of bias within these categories, 16,19,[23][24][25]32,[35][36][37][38][39] when looking at the potential for "other sources" of bias, all were seen as being at high risk due to a number of factors: they offered other analgesics besides the study drugs, recruited women who were looking for IUC placement and, in some cases, there was overlap in the VAS pain scores between treatment and placebo groups or the VAS pain scores in both groups were low (<4).  interventions that result in lower pain scores when compared with placebo or control groups. 16,22,24,25,27,[29][30][31][32][34][35][36][37] The majority of these interventions involve pre-insertion local anesthesia with lidocaine preparations. There is a need, however, for standardization of doses of these local analgesic agents, not only to optimize pain relief but also to maximize safety by preventing spread to vaginal tissue. 31 The studies described reinforce the message that pain with IUC placement is not confined to the insertion of the device; use of the tenaculum and the uterine sound can also contribute to an uncom- and LP cream) and the placebo/control as being clinically relevant. 16,24,27,29,30,32,[35][36][37][38]

| Areas of potential future research
In addition to the ongoing need to evaluate pain-relieving strategies Given that size and flexibility of the IUC can affect pain during placement, using smaller inserters and devices is likely to improve the experience for many women. The studies describing cervical priming showed that a moderate reduction in pain with IUC placement can be achieved with the use of vaginal misoprostol when compared with placebo. 22,24,25 These studies also showed that misoprostol increased the likelihood of successful IUC placement and eased the procedure from a healthcare professional perspective in women who had a history of cesarean delivery or were nulligravi-