The Effect of Nitroglycerin on the Intrauterine Device (IUD) Insertion Experience in Nulliparous Women

Increasing acceptability and use of long acting reversible contraceptive methods like the
intrauterine device (IUD) is an important strategy to reduce the risk of unintended
pregnancy. Unfortunately, fear of IUD insertion in nulliparous women is common among health
care providers and women alike, and this limits IUD use. While many health care providers
assume that placement is more difficult in nulliparous women, there is no evidence that the
risk of unsuccessful insertion is higher. Women worry about pain with insertion, and their
fear is not unfounded as U.S. and international data have shown that nulliparous women
report approximately twice as much pain with IUD insertion compared to parous women.

A key difference between nulliparous and multiparous women is the resistance of the cervix.
While cervical dilation is uncommonly needed during IUD placement, force is often required
to pass the insertion device through the internal os. Although misoprostol and ibuprofen
have been studied as ways to improve the IUD insertion experience, neither has proved
effective, and misoprostol actually has been shown to increase pain. Therefore, to increase
acceptance of this highly effective contraceptive, there is a need to investigate novel, low
cost, easily applied and accessible techniques to improve the insertion experience.

Nitric oxide (NO) donors, including nitroglycerin, nitroprusside, isosorbide mononitrate and
isosorbide dinitrate, have effects on the animal and human cervix. Both nitroglycerin and
isosorbide mononitrate tablets administered vaginally have been shown in RCTs to induce
effective cervical ripening with minimal side effects for first trimester abortion compared
to placebo. Nitroprusside and isosorbide dinitrate gel given intracervically prior to first
trimester abortion also have showed minimal side effects in several RCTs, but with mixed
results regarding effectiveness. Additional safety data about NO donors applied topically to
skin and mucosal surfaces is well established through the routine use of topical
nitroglycerin for treatment of anal fissures.

Although a recent randomized controlled trial (RCT) comparing nitroprusside gel to
misoprostol for cervical ripening prior to first trimester surgical abortion found superior
cervical dilation in the misoprostol group, there was no significant difference in cervical
dilation up to 5 mm. While most studies of abortion are concerned with providing adequate
dilation beyond 8 mm, the cervical remodeling that is necessary to help with IUD insertion
is much less, as the levonorgestrel intrauterine system (LNG-IUS) inserter is only 4.75 mm
in diameter. Since NO donors are smooth muscle relaxants, they are expected to induce
cervical ripening without causing uterine cramping, which is the most significant side
effect of misoprostol.

Nitroglycerin is inexpensive, stable at room temperature, and readily available in tablet
and ointment form, as well as in a dextrose solution for intravenous administration. The
ointment form is commonly applied topically for the treatment of anal fissures. We propose
the following aims:

1. To determine if nitroglycerin ointment applied vaginally 30-45 minutes prior to IUD
insertion improves pain among nulliparous women compared to a placebo ointment.
Self-reported pain scores on a 100 mm VAS will be assessed at multiple time points
during and after the IUD insertion procedure. In addition, overall satisfaction and
adverse effects will be evaluated.

2. To determine if nitroglycerin ointment applied vaginally 30-45 minutes prior to IUD
insertion improves ease of IUD insertion for the provider compared to a placebo
ointment. In addition, need for additional dilation, additional pain medicine such as
paracervical block, inability to place the IUD, and complications will be tracked.

3. To determine if nitroglycerin ointment applied vaginally 30-45 minutes prior to IUD
insertion is safe and well tolerated. Side effects related to treatment with
nitroglycerin ointment or placebo will be compared. Blood pressure will be measured at
multiple time points.

Inclusion Criteria:

1. age 18-45 years,

2. generally healthy,

3. requesting a LNG-IUS for contraception as the primary indication

Exclusion Criteria:

1. Previous pregnancy beyond 20 weeks;

2. previous IUD placement or attempted IUD placement;

3. previous cervical cold knife cone (CKC) or loop electrosurgical excision procedure
(LEEP);

4. contraindication to LNG-IUS (including pregnancy, fibroids that distort the uterine
cavity, exam consistent with PID, allergy to any component of the LNG-IUS, etc);

5. concurrent use of any form of nitrate therapy or medications that interact with
nitroglycerin (such as phosphodiesterase V inhibitors);

6. known allergy to nitroglycerine or common topical ointment ingredients;

7. known renal or hepatic impairment;

8. history of hypertensive or hypotensive disorder;

9. history of migraine, cluster headaches, or vascular headaches;

10. history of myocardial infarction;

11. uncontrolled congestive heart failure;

12. unstable angina;

13. tobacco or alcohol amblyopia;

14. congenital optic atrophy;

15. blood pressure less than 90/55 or greater than 150/100 in office prior to speculum
exam