Medication for Opioid Use Disorder and Perioperative Outcomes for Benign Hysterectomy

Authors: Yongmei Huang, Alicia H. Li, June Y. Hou, Pia M. Mauro, Xiao Xu, Guohua Li, Adam Bisaga, Dawn L. Hershman, Silvia S. Martins, Jason D. Wright

Abstract

Medication for opioid use disorder was associated with reduced perioperative complications among patients with opioid use disorder undergoing hysterectomy, particularly with more than 90 days of medication for opioid use disorder.

Over the past 2 decades, opioid-related overdoses have claimed more than 806,000 lives and resulted in 2.6 million Americans suffering from opioid use disorder (OUD).^1^ Since 1999, opioid overdose deaths have risen 642% among women.^2^ Women with OUD experience great functional impairment, medical complications, and psychiatric issues.^2,3^ From 2016 to 2018, approximately 1.1% of women who underwent hysterectomy had a preoperative OUD diagnosis,^4^ with an estimated 5,500 or more annual cases of OUD among patients undergoing hysterectomy in the United States.^5^

Medication for OUD (MOUD), including methadone, buprenorphine, and naltrexone, have been shown to effectively reduce opioid use and overdose risk.^6^ In addition, MOUD improve outcomes across a range of clinical settings such as improving antiretroviral therapy adherence, rates of viral suppression, and morbidity and mortality among individuals with OUD and human immunodeficiency virus (HIV),^7^ as well as reduced opioid misuse and improved maternal and neonatal outcomes among pregnant women.^8^ However, evidence on the use and effect of MOUD on perioperative outcomes for patients undergoing surgical procedures remains limited.^4,9^

The American Society of Addiction Medicine recommends discontinuing naltrexone (an opioid antagonist) therapy before surgery because it blocks opioid effects for perioperative pain management.^10^ In contrast, dosing of methadone (a full opioid agonist) and buprenorphine (a partial opioid agonist) is individualized to manage withdrawal and cravings.^10^ The continuation of methadone and buprenorphine through the perioperative period has been endorsed in recent literature.^11–13^ We recently demonstrated that among patients with OUD undergoing a variety of surgical procedures, current MOUD use was associated with lower perioperative opioid requirements, a reduced risk of postoperative persistent opioid misuse, and decreased rates of hospital readmissions and emergency department (ED) visits.^4^ However, the association between MOUD and surgical-related outcomes is uncertain.

Given the prevalence of preoperative OUD among women undergoing hysterectomy, optimizing the perioperative management of MOUD in this population is of significant clinical importance. The objective of our study was to evaluate the association between MOUD use and hysterectomy-related complications, morbidities, and health care utilization.

METHODS

We used data from the MarketScan Research Databases, which capture clinical services and expenditure information from more than 270 million unique patients in Commercial Claims and Encounters Database and Multi-State Medicaid Database, including inpatient services, outpatient services, and outpatient pharmaceutical claims.^14^ Because the data from MarketScan datasets are deidentified, this study was classified as nonhuman subjects research by the Columbia University IRB.

The study population included female individuals 18–64 years of age who underwent hysterectomy for benign indications between 2016 and 2021. To capture all services a patient received, we excluded patients who lacked continuous health insurance and prescription drug coverage during the observation period (365 days before through 180 days after surgery). We excluded obstetric patients with delivery codes within 30 days of hysterectomy and patients with gynecologic cancers who had at least two claims more than 30 days apart within a year (Appendix 1, available online at http://links.lww.com/AOG/E498).

Preoperative OUD was identified with International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and 10th Revision (ICD-10-CM) codes. Patients who had a relevant ICD-9-CM/ICD-10 diagnosis code relating to opioid abuse and dependence in the 365 days before surgery were considered to have preoperative OUD^4,15^ (Appendix 1, http://links.lww.com/AOG/E498).

The use of MOUD, including methadone or buprenorphine, was determined from relevant Healthcare Common Procedure Coding System codes, ICD-9-CM and ICD-10-CM codes, and pharmaceutical claims.^15^ Use of MOUD was categorized as prior use (claims within 365 to 31 days before surgery but none within 30 days before surgery) and current use (claims within 30 to 1 day before surgery regardless of prior use, either continually used or newly initiated therapy). Among current users, we categorized their duration of current MOUD as 1–90 days or >90 days before surgery according to data distribution and expert input from psychiatrists specializing in OUD treatments.

Our primary outcomes were hysterectomy-related complications, identified from relevant diagnostic claims from the day of surgery to within 60 days of the procedure. These included three separate binary indicators for any intraoperative complication, any surgical site complication, and any medical complication, as well as a composite binary indicator for any of these complications. Intraoperative complications included vascular, gastrointestinal, genitourinary, and neurologic injuries, as well as the need for reoperation. Surgical site complications included wound infection, abscess, hemorrhage, gastrointestinal bleeding, bowel obstruction, and ileus. Medical complications comprised myocardial infarction, cardiopulmonary arrest, respiratory failure, renal failure, stroke, sepsis, pneumonia, and arrhythmia^16^ (Appendix 1, http://links.lww.com/AOG/E498).

Our secondary outcomes included perioperative opioid use, postoperative persistent opioid use, and postoperative utilization of health services. Outpatient pharmaceutical claims were analyzed to assess perioperative and postoperative opioid prescription. Perioperative opioid use was defined as a fill of any opioid prescription from 30 days before to 2 weeks after the surgical procedure.^17,18^ Total dose and daily dose, measured as morphine milligram equivalents, and supply days of opioids and refills were captured.^17^ Postoperative persistent opioid use after surgery was defined as any prescription fill between 91 and 180 days after surgery.^17,18^ Postoperative utilization of health services included hospital readmission within 30 days and ED visits within 30 and 90 days after the index procedure.^4^

Demographics and baseline factors included year of surgery, age (<40, 40–49, 50–59, 60–64 years), insurance status (commercial, Medicaid), and surgical setting (inpatient or outpatient). Preoperative Elixhauser comorbidities were identified from ICD-9-CM and ICD-10 codes within 31–90 days before surgery.^19^ Other conditions associated with OUD, including other substance use disorder (SUD), chronic pain, anxiety, and depression, were assessed from diagnostic claims from the year preceding surgery.^18^ Chronic pain was defined from at least two claims for relevant conditions occurring more than 30 days apart.^18^

Indications for hysterectomy included abnormal uterine bleeding, leiomyoma, endometriosis, dysmenorrhea, pelvic organ prolapse, benign neoplasms and cysts, endometrial hyperplasia, and cervical dysplasia. A patient could have had more than one indication for hysterectomy. The route of surgery was classified as abdominal, minimally invasive (laparoscopic or robotic assisted), or vaginal. Concurrent surgical procedures such as anterior or posterior repair, incontinence repair, oophorectomy, and other procedures (debulking, lymphadenectomy, small bowel resection, colon resection, rectosigmoid resection, ileostomy, colostomy, liver resection, bladder resection, diaphragm resection, splenectomy, and gastrectomy) were captured (Appendix 1, http://links.lww.com/AOG/E498).

Descriptive analyses were performed for demographic and clinical variables, perioperative opioid exposure, opioid prescription patterns (total dose, daily dose, supply duration, refills), and postoperative outcomes. Categorical variables were compared by presurgical OUD status with χ^2^ or Fisher exact tests in Appendix 2 (http://links.lww.com/AOG/E498); the Bonferroni correction was applied to adjust the significance level. Trends in current MOUD use were examined with Cochran–Armitage trend tests. Multinomial logistic regression models were used to examine factors (including demographics, preoperative factors, and surgical indications) associated with MOUD use (current or prior MOUD use compared with none). These factors were selected from the literature review.^4^ Estimates are reported as adjusted odds ratios (aORs) and 95% CIs.

Propensity score inverse probability of treatment weighting was applied to evaluate the average treatment effect of MOUD on outcomes of interest.^16^ Multinomial logistic regression models were used to calculate the predicted probability of each patient receiving no MOUD, current MOUD, and prior MOUD based on patients' baseline characteristics. Covariates in the multinomial logistic regression model included procedure year, patient age, insurance status, hospital setting, Elixhauser comorbidities, anxiety, depression, other SUD, chronic pain, and individual indications for hysterectomy. Each patient was assigned a weight equal to the inverse of the predicted probability for the treatment they actually received. Balance diagnostics were assessed with Rao–Scott χ^2^ tests based on the weighted cohort. Log-linear Poisson regression models were used to estimate associations between MOUD status and binary outcomes (hysterectomy-related complications, perioperative opioid use, prescription refills, postoperative persistent opioid use, readmissions within 30 days after surgery, and ED visits within 30 days or 90 days after surgery). Model estimates are reported as adjusted risk ratios (aRRs) with 95% CIs. To analyze perioperative opioid prescription differences, multivariable quantile regression models were developed to estimate adjusted median differences (aMDs) and 95% CIs in total opioid dose, daily dose, and supply days during the perioperative period because these variables were not normally distributed. Surgical route and current procedures were further adjusted in the outcome models based on the propensity score inverse probability of treatment–weighted cohort.

In subgroup analyses, we evaluated the association between specific MOUD types (buprenorphine vs methadone) among patients currently using MOUD, as well as the association between MOUD duration (more than 90 days vs 1–90 days) and the outcomes of interest.

All analyses were performed with SAS 9.4.

RESULTS

A total of 153,138 patients who underwent hysterectomy from 2016 to 2021 were identified. Preoperative OUD was noted in 1,715 subjects (1.12%, 95% CI, 1.07–1.17%). Patients with preoperative OUD had a median age of 39 years (interquartile range 34–44 years), and 71.9% were Medicaid beneficiaries. Compared with patients without OUD, those with OUD had more Elixhauser comorbidities and higher risks of anxiety (63.4% vs 23.5%), depression (51.3% vs 16.7%), chronic pain (84.7% vs 51.7%), and other SUD (65.9% vs 12.1%) (all P<.001). Among patients with OUD, the most common indication for hysterectomy was abnormal uterine bleeding (71.8%), followed by endometriosis (51.1%) and benign neoplasms cysts (42.2%). Compared with patients without OUD, patients with OUD were more likely to undergo hysterectomy for dysmenorrhea and cervical dysplasia. Overall, 18.8% of patients with OUD had abdominal, 70.5% had minimally invasive, and 10.7% had vaginal hysterectomy. Approximately 12.0% of patients with OUD had concurrent procedures, most commonly anterior or posterior repair (Appendix 2, http://links.lww.com/AOG/E498).

Among patients with OUD, 28.6% (95% CI, 26.5–30.8%) of patients were current users, and 9.0% (95% CI, 7.7–10.4%) were prior users. Current MOUD use increased over time from 20.5% (95% CI, 16.6–25.1%) in 2016 to 40.7% (95% CI, 33.1–48.7%) in 2021 (P<.001), and the overall increasing trends in MOUD use were similar between Medicaid beneficiaries and patients covered by commercial insurance (P>.05 for the interaction term between procedure year and health insurance) (Fig. 1). Compared with no MOUD use, current MOUD use was associated with Medicaid insurance (aOR 1.57, 95% CI, 1.16–2.13) and more Elixhauser comorbidities. However, patients with chronic pain were less likely to be current MOUD users (aOR 0.26, 95% CI, 0.19–0.36). Patients with pelvic organ prolapse were more likely to be current MOUD users, whereas those diagnosed with benign neoplasms and cysts were less likely to be treated with MOUD (Table 1).

In the propensity score inverse probability of treatment–weighted cohort, patients' demographics and baseline clinical factors were well balanced (Appendix 3, http://links.lww.com/AOG/E498). Patients who were currently receiving MOUD were associated with fewer perioperative complications than nonusers of MOUD (27.7% vs 33.9%, aRR 0.86, 95% CI, 0.76–0.97). This included significantly fewer surgical site complications (12.8% vs 16.9%, aRR 0.82, 95% CI, 0.69–0.98) and fewer medical complications (17.5% vs 22.8%, aRR 0.78, 95% CI, 0.67–0.91) (Table 2).

Patients who were currently receiving MOUD were also less likely than those not receiving MOUD to have perioperative opioids prescriptions (67.6% vs 91.3%, aRR 0.79, 95% CI, 0.73–0.85). Among patients prescribed opioids, current MOUD users had lower median total opioid dose than nonusers (225.0 [interquartile range 150.0–478.0] morphine milligram equivalents vs 626.8 [interquartile range 225.0–1712.5] morphine milligram equivalents), shorter supply duration (7 [interquartile range 4–10] days vs 18 [interquartile range 7–40] days), and fewer opioid prescription refills (31.0% vs 64.2%, aRR 0.64, 95% CI, 0.58–0.72) (Table 3).

Postoperatively, patients who were currently receiving MOUD were less likely than those not receiving MOUD to have persistent opioid use (11.6% vs 51.1%, aRR 0.34, 95% CI, 0.30–0.39) or to experience ED visits within 30 days (19.1% vs 27.7%, aRR 0.72, 95% CI, 0.63–0.83) and 90 days (32.6% vs 42.8%, aRR 0.79, 95% CI, 0.71–0.88) (Table 3). Prior MOUD use was also associated with reductions in total dose of perioperative opioid use, supply duration, and postoperative persistent opioid use compared with nonuse of MOUD. However, prior MOUD use was associated with higher risks of surgical complications than no MOUD use, although these risks were not related to postoperative readmissions and ED visits (Tables 2 and 3).

In subgroup analyses among current users, no differences were observed between buprenorphine and methadone users in hysterectomy-related complications, perioperative opioid use patterns, and postoperative outcomes (Appendixes 4 and 5, http://links.lww.com/AOG/E498).

Compared with patients who were treated with MOUD for 90 days or less before surgery, those who received MOUD for more than 90 days had a lower risk of any surgical complication (27.2% vs 34.2%) and medical complications (16.6% vs 28.9%) and a lower risk of persistent opioid use (10.6% vs 23.7%) and ED visits within 30 days (18.3% vs 28.9%) and 90 days (31.8% vs 42.1%) (Appendixes 4 and 5, available online at http://links.lww.com/AOG/E498).

DISCUSSION

Our study highlights the potential beneficial effects of MOUD among patients with OUD undergoing hysterectomy. Compared with those not using MOUD, patients currently using MOUD had significantly fewer perioperative complications, lower perioperative opioid use, a reduced risk of postoperative persistent opioid use, and fewer ED visits. These findings add to the growing literature on the importance of MOUD uptake across populations with OUD, extending it to improved hysterectomy-related outcomes.

Several factors may contribute to the association between MOUD use and reduced surgical complications. First, MOUD stabilizes opioid receptor activity, preventing withdrawal symptoms, and reduces physiological stress responses.^20^ This can prevent autonomic instability,^21^ which impairs wound healing, cardiovascular stability, and immune function. Second, continued MOUD is associated with improved perioperative pain management, reducing the need for higher-dose perioperative opioids, which can be associated with complications such as respiratory depression.^22^ Third, MOUD-treated patients may demonstrate higher engagement with the health care system,^23^ including better adherence to surgical instructions and postoperative care plans, thereby reducing potentially preventable complications such as infection, wound complications, and readmissions. Last, discontinuation of MOUD has been associated with increased rates of nonmedical opioid use.^20,24^ Together, these mechanisms suggest that MOUD not only supports recovery from OUD but also may confer clinical benefits in surgical populations.

Given the well-established benefits of MOUD, expanding access is essential. However, a substantial treatment gap persists between the number of individuals diagnosed with OUD and those receiving MOUD.^20,25^ In our analysis, only one in four patients with OUD undergoing hysterectomy received MOUD in 2016. Although this rate doubled by 2021, still fewer than half received treatment at the time of surgery. Similarly, a 2021 national survey found that only 22.3% of adults with OUD used MOUD.^26^ Barriers to MOUD access are multifaceted and include lack of health insurance, financial constraints, stigma, and a limited number of buprenorphine prescribers for outpatient care.^2,3^ Women face additional challenges such as childcare responsibilities, limited family support, discrimination, co-occurring psychiatric disorders, trauma history, and economic hardship.^2,3^ We found that Medicaid beneficiaries with OUD were 58% more likely to receive guideline-concordant MOUD compared with patients covered by commercial insurance, which is consistent with prior research.^25^ As OUD has become an increasingly common comorbidity among surgical patients, affecting over 1% of patients undergoing hysterectomy, presurgical counseling presents a unique opportunity to screen for OUD and to plan surgical pain management.^9^ In addition, because obstetrician–gynecologists often serve as their patients' primary care physicians, they are well positioned to diagnose OUD and to initiate and manage MOUD, including prescribing buprenorphine under current federal regulations. Strengthening obstetrician–gynecologists’ willingness to prescribe agonist therapies or to collaborate with addiction medicine or psychiatry specialists, along with targeted education on the perioperative implications of MOUD, could enhance continuity of care and improve surgical outcomes.

Consistent with prior literature,^27^ we found no significant differences in outcomes between methadone and buprenorphine use in subgroup analyses. Most people in our sample used buprenorphine, which reflects other studies of patients covered by commercial insurance.^8,9^ Buprenorphine is preferable for several reasons.^28^ First, buprenorphine has a more favorable safety profile. As a partial opioid receptor agonist, buprenorphine activates opioid receptors to a lesser extent than full agonists such as methadone, producing a ceiling effect that lowers the risk of respiratory depression and fatal overdose.^20,28^ Second, buprenorphine offers greater accessibility and flexibility. Buprenorphine can be prescribed in primary care and outpatient settings by trained clinicians, whereas methadone is limited to federally regulated opioid treatment programs that often require daily visits during early treatment.^20,28^ The use of buprenorphine not only reduces logistical barriers but also minimizes stigma by allowing patients to receive MOUD from their regular health care professionals instead of specialized clinics. However, methadone may be more appropriate clinically for patients who have higher doses of heroin use or fentanyl use if they have a high risk of dropout or overdose.^10^

Guidelines recommend that the duration of MOUD treatment should be individualized, considering clinical stability, patient preference, risk of relapse, and life circumstances.^8,10^ Discontinuation or rapid tapering is discouraged because of the high risk of relapses and overdose.^24^ Current evidence suggests that longer durations of MOUD are associated with better outcomes.^24,29,30^ However, there is a lack of consensus on when to discontinue MOUD maintenance treatment. The definition of long-term treatment duration has varied.^29^ Burns et al^29^ found that patients who continued MOUD beyond 60 days had a lower relative hazard of overdose compared with those who discontinued by day 60; in addition, the hazard of overdose decreased by 10% with each additional 60 days of MOUD. In our study, 92.3% of MOUD users received MOUD for more than 90 days before surgery, and these patients had lower risks of any surgical and medical complications and significantly lower postoperative persistent opioid use and ED visits compared with those treated for 90 days or less. Therefore, delaying elective hysterectomy until patients with OUD are on a stable MOUD regimen may be warranted.

Although our study represents a large sample of patients with OUD undergoing hysterectomy, we acknowledge several limitations. First, we were unable to capture MOUD administered outside the health insurance system. For example, if a patient received methadone treatments through a federally funded opioid treatment program without insurance billing, their MOUD use would not be reflected in the claims data. Second, our study measured opioid use according to outpatient pharmaceutical claims for prescriptions filled; however, the presence of a prescription does not guarantee that the medication was consumed. Third, the MarketScan dataset lacks information on medication prescribers, preventing us from assessing whether clinician characteristics influenced MOUD provision. This approach also limits our ability to capture nonmedical use of opioids. Fourth, our analysis was limited to patients 64 years of age or younger with benign indications, so the findings may not be generalizable to older populations or patients with cancer. Finally, because unmeasured confounders could not be accounted for with observational data, our findings should be interpreted cautiously as associations rather than causation.

In conclusion, OUD has emerged as an increasing comorbidity among patients undergoing hysterectomy, yet gaps remain in the receipt of guideline-concordant MOUD. Among patients with OUD undergoing hysterectomy, MOUD is associated with reduced perioperative complications. Methadone and buprenorphine provide comparable treatment effects, and the choice should be guided by patient needs and the availability of care. At least 3 months of MOUD treatment optimizes postsurgical outcomes, supporting the importance of treatment retention.