Prescription Opioid Use in Women with Endometriosis

MARGARET WESTPHAL, BA 

Drexel University College of Medicine

SUMMARY POINTS

• Endometriosis is a growth of endometrial tissue outside the uterine cavity that is not well understood.

• Treatment for endometriosis involves both oral medication and surgery, but since neither modality is curative, long-term pain management may be required.

• Women with endometriosis receive nearly one quarter (24%) of the opioid medication prescribed by U.S. obstetric-gynecologists. 

• Women with endometriosis are at an increased risk of chronic opioid use, and benefit-risk decision making should be used by physicians for disease management. 

ANALYSIS 

Background

Endometriosis is a common gynecological condition characterized by a growth of endometrial tissue outside of the uterine cavity, a mechanism that is currently still poorly understood (5). A possible pathophysiology of retrograde menstruation has been suggested, although still subject to debate (2,7). It affects between 6-10% of women of reproductive age, and can result in dysmenorrhea, pelvic pain, and/or infertility due to the estrogen-dependent chronic inflammation caused by the presence of ectopic tissue (4). Estrogen allows for the continued survival of endometrial lesions that promote the production of cytokines and prostaglandins that characterize inflammation and pain (9). The extent of the resulting pain varies according to location and depth of lesions and association with innervated areas (9). 

Endometriosis is diagnosed through a combination of medical history, physical exam, and laparoscopy (8). There is often a delay between the onset of symptoms and a medical diagnosis, reported to be between 7 to 12 years (8). Pelvic pain should immediately signal to providers that further investigation should be made into a potential endometriosis diagnosis. A physical exam should be done to determine size and position of the uterus, as well as biomarker testing for CA-125, a cancer antigen that may be elevated in severe to moderate disease (8). The gold standard for diagnosis is laparoscopy, which allows for identification of the location and severity of the disease but is not always required in non-surgical treatments when endometriosis is strongly suspected (9).

There is currently no cure for endometriosis. Treatment for endometriosis involves two modalities, medications and ablative surgery, both focused on allowing patients to manage chronic pain and treat symptoms of the disease (10). Oral contraceptives are the first-line treatment for patients, while second line treatment involves gonadotropin-releasing hormone analogues and aromatase inhibitors (5). Of note, these therapies disrupt ovulation and future pregnancy must be considered for patients before prescribing (5). Of these drug treatments, studies have shown that they do not differ in terms of their ability to relieve pain; however, around 30-60% of endometriosis patients do not respond to these conventional options (8).

The goal of surgical intervention for painful endometriosis that is unaffected by medical treatment is removal of ectopic endometrial tissue (9). Laparoscopic excision or ablation of lesions have been clinically proven to help reduce pain load for patients with mild to moderate disease burden (4). In more severe cases, the ovaries and the uterus may require removal (9). However, a fairly large proportion of women, between 20% to 40%, may not show improvement after surgery and require management of pain on a longer-term basis (8).

Figure 1. Pain and neurogenic inflammation in endometriosis. SEE ARTICLE from Guan, Qihui, et al. “Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?” International Journal of Molecular Sciences, vol. 24, no. 2, 2023, p. 1633, https://doi.org/10.3390/ijms24021633. 

Analysis

Pain is the major symptom of endometriosis, which can manifest as painful menstruation, intercourse, micturition, and chronic pelvic pain (8). As a result of both post-surgical intervention and chronic pain management, women with endometriosis receive nearly one quarter (24%) of the opioid medication prescribed by U.S. obstetric-gynecologists (6). As such, women with endometriosis are at an increased risk of chronic opioid use, and benefit-risk decision making should be used by physicians for disease management. A retrospective cohort study covering over 150 million individuals in the United States found that women with endometriosis were more likely to fill at least one prescription for an opioid vs women without (70.3% vs 24.2%), as well as being more likely to have filled multiple opioid prescriptions (40.3% vs 10.5%) (6). 

Women with endometriosis were also more likely to have filled prescriptions for opioids and benzodiazepines concomitantly and more likely to have the supply extended for 7 days, 30 days, or 90 days (6). Opioids and benzodiazepines are both drugs with a high likelihood of abuse worldwide and patients taking both agents at the same time are estimated to have a 10x greater risk of overdose than those taking opioids alone (6). 

Data shows that women with endometriosis were more likely to fill an initial opioid prescription, including for a short supply for post-operative pain management (6). 76.2% of patients filled an opioid prescription within 7 days of endometriosis-related surgery (6). In addition, patients undergoing robotic surgery for endometriosis used over twice as many opioids postoperatively as patients without the disease and were reported to experience larger amounts of pain after surgery (3). In an analysis excluding prescriptions filled within 30 days post-surgery, women with endometriosis were also more likely to have filled an opioid prescription than women without (45.1% vs 23.6%) and to have filled multiple prescriptions (23.6% vs 10.2%) (6). This signifies that opioids are being prescribed for pain management of endometriosis outside of post-operative care, a treatment strategy that is not currently recommended due to the potential for long-term harm.

Based on this collected data, the 2-year risk for chronic opioid use was estimated to be 4.4%, a four-fold greater risk of chronic opioid use compared to women without the disease (1). Part of this risk may be attributed to the multimorbidity attributed to the disease, which increased the risk of opioid use to manage multiple pain-related conditions including back pain, migraines, irritable bowel syndrome, fibromyalgia, etc. (1). The significant association between endometriosis and risk of chronic opioid use warrants examination by providers and assessment of risk when prescribing opioids for post-surgical or severe pain management.

Discussion

Women with endometriosis have a higher reported incidence of filling a prescription for an opioid, as well as filling longer-term prescriptions for higher doses or concomitant prescriptions for benzodiazepines, even after excluding post-surgery prescriptions for endometriosis-related surgery (6). To combat the risk of chronic opioid use in women with endometriosis, further research is needed into the pathophysiology of the disease and potential treatment methods. Until a curative treatment is available to patients, physicians should strive to help patients with endometriosis develop opioid-sparing pain management strategies. Although some opioid use may be unavoidable, especially in patients undergoing laparoscopic surgery, use should be carefully monitored. In addition, prescribers should be aware of the risk profile of this patient group for potential long-term opioid use and strive to keep postoperative opioid use to a minimum. Unfortunately, like many areas of women’s health, endometriosis remains an area of gynecology that is under-researched and poorly classified. The first step towards reducing pain burden for female patients may perhaps lie in closing the gap between onset of symptoms and diagnosis in order to afford patients the best options for treatment.

REFERENCES:

1. Chiuve, Stephanie E., et al. “Chronic Opioid Use and Complication Risks in Women with Endometriosis: A Cohort Study in U.S. Administrative Claims.” Pharmacoepidemiology and Drug Safety, vol. 30, no. 6, 2021, pp. 787–796, https://doi.org/10.1002/pds.5209. 

2. CRAMER, DANIEL W., and STACEY A. MISSMER. “The Epidemiology of Endometriosis.” Annals of the New York Academy of Sciences, vol. 955, no. 1, 2002, pp. 11–22, https://doi.org/10.1111/j.1749-6632.2002.tb02761.x. 

3. Delgado, Stephanie I., et al. “Postoperative Opioid Use for Patients with Chronic Pelvic Pain Undergoing Robotic Surgery for Resection of Endometriosis.” Journal of Robotic Surgery, vol. 16, no. 2, 2021, pp. 421–427, https://doi.org/10.1007/s11701-021-01259-8. 

4. Furness, Susan, et al. “Pre and Post-Operative Medical Therapy for Endometriosis Surgery.” Cochrane Database of Systematic Reviews, 2004, https://doi.org/10.1002/14651858.cd003678.pub2. 

5. Guan, Qihui, et al. “Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?” International Journal of Molecular Sciences, vol. 24, no. 2, 2023, p. 1633, https://doi.org/10.3390/ijms24021633. 

6. Lamvu, Georgine, et al. “Patterns of Prescription Opioid Use in Women with Endometriosis.” Obstetrics & Gynecology, vol. 133, no. 6, 2019, pp. 1120–1130, https://doi.org/10.1097/aog.0000000000003267. 

7. Lebovic, Dan I, et al. “Immunobiology of Endometriosis.” Fertility and Sterility, vol. 75, no. 1, 2001, pp. 1–10, https://doi.org/10.1016/s0015-0282(00)01630-7. 

8. Leyland, Nicholas, et al. “Endometriosis: Diagnosis and Management.” Journal of Endometriosis, vol. 2, no. 3, 2010, pp. 107–134, https://doi.org/10.1177/228402651000200303. 

9. Olive, David L., and Elizabeth A. Pritts. “Treatment of Endometriosis.” New England Journal of Medicine, vol. 345, no. 4, 2001, pp. 266–275, https://doi.org/10.1056/nejm200107263450407. 

10. VALLE, RAFAEL F., and JOHN J. SCIARRA. “Endometriosis: Treatment Strategies.” Annals of the New York Academy of Sciences, vol. 997, no. 1, 2003, pp. 229–239, https://doi.org/10.1196/annals.1290.026.