Ketorolac use after oocyte retrieval: doing our part to combat the opioid crisis

The opioid epidemic claims nearly 50,000 lives per year and is associated with an annual economic cost of more than $80 billion in the United States alone (1). Surgery represents a critical time when both opioid-tolerant and opioid-naïve patients are exposed to narcotics, risking opioid-related adverse events and future opioid-use disorder. Studies demonstrate significantly higher rates of chronic opioid use after even minor surgeries compared with the baseline rates of new persistent use among non-postoperative populations (5.9% vs. 0.4%) (2).

Consequently, strategies to limit or eliminate the acute use of opioids in the perioperative setting have become increasingly championed across several surgical disciplines, including obstetrics and gynecology. The modification of clinical practice to use multimodal, proactive approaches to analgesia that minimize intraoperative and postoperative use of narcotics, without compromising recovery rates or adequate treatment of postoperative pain, is being widely adopted and studied. Nonsteroidal anti-inflammatory drugs, such as ketorolac, serve as popular alternatives to narcotic pain medications, with favorable safety, efficacy, adverse events, and cost profiles.

Even low-risk surgeries, such as the nearly 200,000 transvaginal oocyte retrievals performed annually by reproductive endocrinology and infertility physicians in the United States, provide an opportunity to reduce unintended contributions from infertility care to the opioid epidemic. Despite the undeniably devastating effects of widespread opioid abuse and general sense of shared responsibility within the medical community to curb the epidemic, there is heterogeneity in comfort using ketorolac routinely after oocyte retrieval. Ketorolac is a nonselective cyclooxygenase inhibitor. Unlike other surgeons who typically only balance adequate postoperative pain and bleeding risk concerns given ketorolac’s antiplatelet properties, reproductive endocrinology and infertility providers face an additional challenge; the implications of all therapeutic interventions must be considered in the context of an imminent embryo transfer and subsequent pregnancy outcomes.

The failure of embryo implantation remains a persistent challenge during fertility treatment. The routine use of nonsteroidal anti-inflammatory drugs at the time of oocyte retrieval, days before a potential fresh embryo transfer, has been scrutinized because of the importance of prostaglandins during endometrial decidualization and embryo implantation. Nonselective cyclooxygenase inhibitors like ketorolac have been theoretically hypothesized to compromise pregnancy outcomes because cyclooxygenase is the rate-limiting enzyme in the synthetic pathway converting arachidonic acid into prostaglandins, despite its half-life of 4–7 hours.

In this issue of F&S Reports, Seidler et al. (3) presented results from a large retrospective cohort study at a single center comparing patient narcotic requirements, postoperative complications, and pregnancy outcomes after fresh embryo transfer after oocyte retrieval from 2 distinct time periods between which there was an institutionalized change to routinely administer 30 mg of intravenous ketorolac after oocyte retrieval. Overall, patients from each time period did not differ with respect to baseline demographics, ovarian reserve, or in vitro fertilization cycle characteristics. The study demonstrated a statistically significant decreased use of postprocedural narcotics among 1,780 patients receiving ketorolac compared with 826 patients in the non-ketorolac group (25.5% vs. 12.0%), with no difference in postoperative bleeding complications. Although not the primary outcome of the study, the investigators also reported that among approximately 50% of the patients in each group who proceeded to undergo a fresh embryo transfer, there appeared to be no compromise in clinical pregnancy rate (32.4% in the ketorolac group vs. 32.6% in the non-ketorolac group) or live birth rate (26.3% in the ketorolac group vs. 28.8% in the non-ketorolac group).

This study is certainly not without limitations, largely inherent to its retrospective design, which has similarly limited the reliability of previous studies in this content area. For example, Mesen et al. (4) analyzed a group of 454 patients undergoing in vitro fertilization over a much longer time span of 6 years, a subset of whom received ketorolac at the discretion of the anesthesiologist. Pregnancy outcomes were reported between patients receiving and not receiving ketorolac at the time of oocyte retrieval, with no differences observed between the 2 groups. The study design of Seidler et al. (3) leveraged an institutionalized protocol change to address the efficacy and safety ketorolac; although still retrospective, it has inherent strengths compared with prior studies. The single-center pre- and post-intervention design works to their advantage because it may limit the variability in ketorolac administration and avoid discretional use of ketorolac that could introduce bias into the study. Additionally, the large cohort was assembled over an otherwise narrow time frame (approximately 1 year) because of the high volume of the center, reducing the influences of other concurrent protocol or general practice changes inherent to the dynamic field of assisted reproduction.

The public health implication of more widespread ketorolac use is significant to consider on the basis of the current findings. If the results of Seidler et al. (3) were extrapolated nationally, an estimation of the cumulative reduction in narcotic exposure during the approximately 150,000 oocyte retrievals reported on the basis of the 2016 Assisted Reproductive Technology National Summary Report is possible. Of the 150,000 patients undergoing oocyte retrieval, only 18,000 compared with 37,500 patients would be exposed to narcotics after adopting routine use of ketorolac. A large national insurance claims database found new persistent opioid use to be 5.9% after minor surgical procedures (2). With routine administration of ketorolac, potentially >1,000 new persistent opioid users could be avoided annually. The magnitude of this benefit will likely only increase, given the rise of infertility treatments. Furthermore, this large study found that the predictors for persistent opioid use were less related to the surgery type (minor vs. major) and more dependent on underlying patient-level comorbidities including mood, anxiety, and chronic pain disorders seen commonly among patients with infertility (2).

This study offers critical insights on the basis of a large cohort and considers all of the competing interests at stake that have, to this point, underpinned controversy regarding the widespread use of nonsteroidal anti-inflammatory drugs for patients with infertility after oocyte retrieval: the effect on pregnancy and live birth after embryo transfer; the risk of increasing postoperative complications; and the opportunity to decrease postoperative pain/narcotic use. Although reproductive endocrinology and infertility providers could previously extrapolate safety data regarding postoperative bleeding risk from other disciplines, there has been a paucity of high-quality large-scale data specific to ketorolac use in this patient population on reproductive outcomes. Reporting both clinical pregnancy and live birth rates offers some of the strongest available evidence defending post-retrieval ketorolac use, with no adverse effects on either implantation or placentation found in this large cohort. Complex health crises, like the opioid epidemic, require a comprehensive and multidisciplinary approach where all prescribers should consider ways to reduce opioid use and potential abuse. Future well-designed prospective randomized controlled trials should be performed to confirm these findings of retrospective cohorts, but until that time, this study provides much needed reassurance and compelling defense of routine ketorolac use after oocyte retrievals, with an opportunity to positively contribute to addressing the opioid crisis.