Which medication and when should it be administered for reducing pain in IUD insertion? We still need further research

Ahmed Said Alia*, Ahmed M. Abdelhakimb, Ahmed SA Ashourc

a MBBCh., Faculty of Medicine, Al-Azhar University, Cairo, Egypt.

b MBBCh., Kasr Al-Ainy, Faculty of Medicine, Cairo University, Cairo, Egypt.

c (MD), Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Cairo, Egypt.

* Correspondence:

Name: Ahmed Said Ali.

Institution: Faculty of Medicine, Al-Azhar University, Cairo, Egypt.

Institutional address: Madinet Nasr, Abbassia, and Cairo, Egypt (Postal code: 11651)

Home address: mokattum city, Cairo, Egypt (Postal code: 11571)

Email: ahmedsaidali987@gmail.com

Mobile: +201125930140

ORCID: 0000-0001-9616-3709

Running title: IUD insertion

Keywords: IUD, Pain, Multipara, Nulligravida, IUD Insertion.

Grants/fellowships supporting the writing of the paper: None.

Disclosure summary: No conflict of interest.

Long-acting reversible contraceptives (LARC), including levonorgestrel-releasing intrauterine system (LNG-IUS) and copper intrauterine device (Cu-IUD), are highly effective, safe, and cost-effective in preventing pregnancy with a low failure rate similar to that of sterilization (1). However, fear of pain and difficulties at insertion are the main obstacles that may preclude IUD counseling and utilization, especially in nulliparous women and women with previous cesarean delivery (CD) (1).

The level of pain that women experience is highly variable, making it difficult to predict the level of discomfort that an individual is likely to experience or the need for pain relief (2). Although there is evidence that nulliparous women (nulligravidas and those who have been pregnant but never given birth) may experience more placement-related pain than their parous counterparts, the majority experience a level of pain that is similar in intensity to that of menstruation(2). Moreover, a proportion of both nulliparous and parous women might experience severe insertion-related pain and such individuals need effective pain relief (3,4).

Cervical ripening agents such as misoprostol and dinoprostone had beneficial effects in reducing pain and facilitating transcervical procedures such as office hysteroscopy (OH) (5–7) and IUD insertion (1,5,8,9). Dinoprostone is a synthetic preparation that is chemically and structurally identical to Prostaglandin E2 (PGE2). Dinoprostone facilitates remodeling of cervical extracellular collagen, increasing water content, and promoting changes in the glycosaminoglycan content of the cervical extracellular content (10). Together, these effects cause changes in cervical consistency with subsequent softening, effacement, and dilation of the cervix. Dinoprostone-induced cervical dilation is the result of cervical tissue remodeling and uterine contractions. By these local effects, dinoprostone could decrease pain and facilitate transcervical procedures (1,11,12) such as IUD insertion.

Based on our studies, dinoprostone had beneficial effects in reducing IUD insertion pain and facilitating the procedure for clinicians in different study populations such as nulliparous women (5,13), women delivered only by CD (1), and parous women (14). Our studies agreed with numerous studies in the literature addressing the value of cervical ripening agents in the context of IUD insertion. Similarly, misoprostol, which exerts a similar cervical ripening effect on the cervix as dinoprostone, was found effective in relieving IUD insertion pain in different study populations; in women with previous cesarean delivery (15,16), in nulligravid women (9), and parous women (17).

Upon literature searching, there is no optimal timing of dinoprostone administration before transcervical procedures. Dinoprostone was found effective at different timings prior to IUD insertion(1,5,13) and at different timings prior to OH(18–20). Similarly, misoprostol was effective when administered at different timings such as 3,4, and 6 hours prior to IUD insertion (9,15–17). Although the onset of action of vaginal dinoprostone suppository starts within 10 minutes and the duration of action lasts for up to 2-3 hours(14). Yet, the cervical ripening effect of dinoprostone is believed to extend beyond the duration of its action. This was evident in studies which found an  effectiveness of vaginal dinoprostone when administered 6 or 12 hours prior to IUD insertion (5,13).

We believe that 2 hours’ time interval is the shortest interval for dinoprostone administration prior to IUD insertion to produce a reasonable cervical ripening effect. It is better to wait for longer durations to obtain the maximal dinoprostone-induced cervical ripening and remodeling because histologic and immunohistochemical studies revealed the presence of dense collagen fibers in the cervical tissues of nonpregnant women(6). The concentration of collagen in the cervix at 10 weeks of gestation and at full term are, respectively, 70% and 30% of the concentration of collagen in the nonpregnant cervix(6). The more time interval between dinoprostone administration and IUD insertion, the more local effects of dinoprostone on cervical softening and dilatation, and consequently, more pain reduction and easier IUD insertion.

A systematic review and meta-analysis by Tassi et al. (8)  evaluated the effect of misoprostol administration on IUD insertion pain and reported that women taking misoprostol ≤ 2.5 h before IUD insertion had a higher VAS pain score compared with the placebo group. Misoprostol exerts a similar cervical ripening effect as dinoprostone. Moreover, Fouda et al. (6) found that vaginal misoprostol given 12 hours before OH was more effective in relieving pain and facilitating the procedure than when it was given 3 hours prior to OH in nullipara. The plasma concentration of vaginal misoprostol increases gradually, reaching its maximum level after 70-80 minutes before slowly declining with the detectable drug levels still present after 6 hours (21).

We agree with Dr. Zeev Blumenfeld that optimal timing of vaginal dinoprostone administration before IUD insertion has not yet been established and needs further investigation. Additionally, we also agree with Dr. Zeev Blumenfeld that the literature lacks comparative studies between misoprostol and dinoprostone in the context of IUD insertion, which we recommend in future studies; the present studies in the literature compare either dinoprostone or misoprostol with placebo. Vaginal dinoprostone was previously compared to vaginal misoprostol administration prior to OH with either superior (18) or comparable efficacy results (19).

Although we believe that every patient having IUD insertion deserves some form of analgesia, the practical clinical question of whether dinoprostone is necessary before any IUD insertion or only for those patients who have not experienced any previous vaginal delivery cannot be answered with a single randomized controlled trial (RCT) of dinoprostone administration prior to IUD insertion in every study population. Multi-center RCTs with larger sample sizes are needed to confirm its efficacy and safety in different study populations and with different IUD types. Additionally, comparative studies between misoprostol and dinoprostone regarding efficacy, safety, and cost-effectiveness are needed to clinically answer the question of generalizability before IUD insertion.

Finally, it is important to consider that our studies regarding dinoprostone administration prior to IUD insertion were performed by different research groups, not by the same group; however, they were led by a common principal investigator (PI), who had previous expertise in research work, family planning, multi-tasking, and research team management. In those research projects, the PI defined the goals, planned the studies designs, recruited different research teams, distributed team members over the different research projects, determined the time plans, assigned tasks, responsibilities, and expectations for the sharing investigators at the beginning of the studies. This was done to maintain the integrity of research works, proper study design, and minimize bias across the studies.

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