Update on pharmacologic treatment for endometriosis-related pain
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Continuing Education
Update on pharmacologic
treatment for endometriosis-
related pain
By Caitlin Henderson, MSN, RN, WHNP-BC, and
Jennifer Hofmann, MS, PA-C
Faculty: Caitlin Henderson, MSN, RN, WHNP-BC, is a 3. Discuss nonpharmacologic treatments for endometriosis-
women’s health nurse practitioner in a private ob/gyn practice in related pelvic pain.
West Islip, New York. Accreditation statement: This activity has been evaluated
Jennifer Hofmann, MS, PA-C, is a physician assistant and and approved by the Continuing Education Approval Program
Associate Clinical Professor at Pace University College of Health of the National Association of Nurse Practitioners in Women’s
Professions in New York, New York. Health (NPWH) and has been approved for 1.0 contact hour of
CE credit, including 0.5 hours of pharmacology credit.
Intended audience: This continuing education (CE) activity has
been designed to meet the educational needs of nurse practitioners Faculty disclosures: NPWH policy requires all faculty to
and other healthcare providers who provide primary care for women. disclose any affiliation or relationship with a commercial inter-
est that may cause a potential, real, or apparent conflict of in-
CE approval period: Now through June 30, 2022
terest with the content of a CE program. NPWH does not imply
Estimated time to complete this activity: 1 hour that the affiliation or relationship will affect the content of the
CE approval hours: 1.0 contact hour of CE credit, including CE program. Disclosures provide participants with information
To participate in this CE program, click hereA.
0.5 contact hours of pharmacology content that may be important to their evaluation of an activity. In ad-
dition, faculty will identify any unlabeled/unapproved uses of
Goal statement: Nurse practitioners and other healthcare drugs or devices discussed in their presentations.
providers who provide primary care for reproductive-aged Caitlin Henderson, MSN, RN, WHNP-BC, has no actual or poten-
women will increase their knowledge about pharmacothera- tial conflicts of interest in relation to the contents of this article.
peutic options and nonpharmacologic approaches for the man- Jennifer Hofmann, MS, PA-C, has no actual or potential con-
agement of endometriosis-related pelvic pain. flicts of interest in relation to the contents of this article.
Needs assessment: Endometriosis is one of the most common Disclosure of unlabeled/unapproved use: NPWH pol-
causes of chronic pelvic pain in reproductive-aged women. It can icy requires authors to disclose to participants when they are
adversely affect quality of life, daily activities, work and school pro- presenting information about unlabeled use of a commercial
ductivity, and both sexual and nonsexual relationships. Nurse prac- product or device, or an investigational use of a drug or de-
titioners and other healthcare providers who provide primary care vice not yet approved for any use.
for reproductive-aged women need to be knowledgeable about
and able to make appropriate choices regarding pharmacothera- Disclaimer: Participating faculty members determine the
peutic options and nonpharmacologic therapy for individualized editorial content of the CE activity; this content does not neces-
care of women suffering from endometriosis-related pelvic pain. sarily represent the views of NPWH. This content has undergone
a blinded peer review process for validation of clinical content.
Educational objectives: At the conclusion of this educa- Although every effort has been made to ensure that the in-
tional activity, participants should be able to: formation is accurate, clinicians are responsible for evaluating
1. Identify risk factors, common symptoms, and physical exam- this information in relation to generally accepted standards in
ination findings associated with endometriosis. their own communities and integrating the information in this
2. Describe indications, mechanism of action, efficacy, adverse activity with that of established recommendations of other
effects, and contraindications for pharmacologic options in authorities, national guidelines, FDA-approved package inserts,
treating endometriosis-related pelvic pain. and individual patient characteristics.
6 June 2020 Women’s Healthcare NPWomensHealthcare.com
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Commercial support: No commercial support was supplied
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Before reading the article, click hereA to take the pretest. Risk factors
These include early menarche;
E
nulliparity; family history of endo-
ndometriosis is one of the most common causes of chronic metriosis, especially in first-degree
pelvic pain in reproductive-aged women. Treatment for relatives; and low body mass index.6
This disorder primarily affects repro-
endometriosis can be pharmacologic, surgical, or both.
ductive-age females, including ado-
In this article, the authors focus on current pharmacologic lescents. In fact, endometriosis is the
options for endometriosis-related pelvic pain and also discuss most common cause of secondary
nonpharmacologic approaches. dysmenorrhea among adolescents.7
Key words: endometriosis-related pelvic pain, NSAID, hormone Diagnosis
therapy, gonadotropin-releasing hormone agonist, aromatase The gold standard for diagnosis of
inhibitor, gonadotropin-releasing hormone antagonist endometriosis is direct laparoscopic
visualization of characteristic le-
sions and/or excision of lesions for
Endometriosis, characterized by the Background histologic evaluation. Lesions can
appearance of endometrial implants Endometriosis is a chronic inflam- be subtle and may be missed by
outside the uterine cavity, is one of matory disorder that is estrogen de- laparoscopy, and surgical evaluation
the most common causes of chronic pendent and commonly associated may not be feasible for or desired
pelvic pain (CPP), affecting 5% to with dysmenorrhea, dyspareunia, by some women.8 Although not
10% of reproductive-aged women.1 and infertility in addition to CPP.3 definitively diagnostic of endome-
More than half of women with CPP The etiology of endometriosis is triosis, common symptoms include
and 15% to 50% of those with infer- not well understood. The disorder dysmenorrhea, CPP, and dyspareunia.
tility have endometriosis.2 Endome- is characterized by growth of endo- Common physical examination find-
triosis-related pelvic pain (ERPP) can metrial cells or implants outside the ings include uterosacral nodularity,
adversely affect quality of life, daily uterus, usually on pelvic structures fixed retroverted uterus, and adnexal
activities, work and school produc- and most commonly on the ovaries. enlargement. Pelvic ultrasonography
tivity, and both sexual and nonsexual Suggested mechanisms by which may help rule out other causes of
relationships. Endometriosis can be these endometrial implants cause these symptoms and exam findings.
treated pharmacologically, surgically, pain include local overproduction of
or with both medication and surgery. prostaglandins as a result of activated Pharmacotherapy
In this article, the authors focus on macrophages and increased cyclo- First-line treatments
pharmacologic options for ERPP and oxygenase-2 activity, direct and indi- Low-risk first-line pharmacotherapy
discuss drug efficacy, safety, contrain- rect effects of active bleeding from may be initiated based on the pres-
dications, tolerability, and cost-effec- the implants, and irritation of pelvic ence of mild-to-moderate symptoms
tiveness. floor nerves.4,5 and examination and ultrasound
NPWomensHealthcare.com June 2020 Women’s Healthcare 7
First-line
pharmacotherapy for every 8 hours; naproxen sodium 440 reductions.13,14 Although COCs are
to 550 mg initially, followed by 220 effective in treating ERPP, recurrence
pain management can to 550 mg every 12 hours; and me- rates following treatment discontinu-
fenamic acid 500 mg initially, followed ation are high.4,5
be initiated based by 250 mg every 6 hours.7,12 NSAID All of the CHCs are generally well
use may be most effective when tolerated. The most common side
on the presence of started 1 to 2 days before menses on- effects are nausea, bloating, breast
set and continued through the first 2 tenderness, and unscheduled/break-
mild-to-moderate to 3 days of bleeding.7
Contraindications to NSAID use
through bleeding, which often re-
solve after the initial few months of
symptoms and include a history of gastrointestinal treatment. Contraindications to CHC
bleeding, other bleeding disorders, use for treatment of ERPP are the
examination and cardiovascular disease, hepatic
disease, renal impairment, and as-
same as those when CHCs are con-
sidered for use as contraceptives.15
ultrasound findings
pirin-sensitive asthma.10 The most
common adverse effects are nausea, Progestin-only contraceptives
indigestion, headache, drowsiness, Depot medroxyprogesterone acetate
that rule out other dizziness, and mouth dryness.10 (DMPA) and the etonogestrel subcu-
Although NSAIDs can ease dys- taneous implant have been shown
potential causes. menorrhea, they do not suppress to be effective in reducing ERPP and
estrogen-dependent endometrial are useful in women who cannot
findings suggestive of endometrio- growths and are often combined tolerate or have contraindications to
sis.9 Choice of pharmacotherapy for with hormone treatment. estrogen.5,16 The main mechanism of
ERPP is based on patient preference action of these POCs in terms of their
and reproductive plans, as well as Combination hormonal ability to reduce ERPP is prevention
medication efficacy, safety, side contraceptives of endometrial proliferation and
effects, and cost. First-line options CHCs containing estrogen and a ovulation, which results in reduction
for mild-to-moderate ERPP include progestin suppress ovarian function, in the production of prostaglan-
nonsteroidal anti-inflammatory leading to atrophy of endometrial dins. Amenorrhea is common with
drugs (NSAIDs), combined hormonal tissue and a reduction in estrogen- ongoing use of POCs.4,5 DMPA is
contraceptives (CHCs), and proges- induced production of prostaglan- administered intramuscularly (IM) or
tin-only contraceptives (POCs). dins. CHCs are available in oral pill, subcutaneously (SC) every 3 months.
transdermal patch, and vaginal ring The subcutaneous DMPA injection
NSAIDs delivery systems and are dosed con- product was approved by the US
The primary mechanism of action of tinuously or cyclically. Although the Food and Drug Administration (FDA)
NSAIDs is inhibition of prostaglandin mechanism of action of hormones for the treatment of ERPP in 2005.
production. Data are inconclusive delivered orally, transdermally, or The etonogestrel implant is placed
regarding whether NSAIDs are effec- vaginally is essentially the same, SC under the skin of the upper inner
tive in relieving ERPP or whether any most available studies have focused arm and may be used for up to 3
particular NSAID is more effective on combination oral contraceptives years. This product has not been FDA
than others.10,11 NSAIDs have been (COCs). Multiple clinical trials have approved to treat ERPP.
shown to be effective in treating demonstrated the superior efficacy Common adverse effects of DMPA
mild-to-moderate primary dysmen- of COCs versus placebo in reducing include irregular spotting/bleeding,
orrhea, however, and are generally ERPP.9 No available evidence sup- mood changes, and weight gain. Re-
well tolerated and cost effective.6 Al- ports the superiority of one COC versible bone loss has been reported
though no specific NSAID dosages are formulation over another in reducing with long-term use of DMPA. The
recommended for treating endometri- dysmenorrhea. In some studies, how- most commonly reported adverse
osis-associated dysmenorrhea, those ever, continuous-dose COC regimens, effect of the etonogestrel implant is
recommended for treating primary as compared with cyclic-dose regi- irregular spotting/bleeding. Contra-
dysmenorrhea include ibuprofen 800 mens, have been shown to provide indications to use of DMPA and the
mg initially, followed by 400 to 800 mg quicker effects and greater pain score etonogestrel implant for treatment
8 June 2020 Women’s Healthcare NPWomensHealthcare.comof ERPP are the same as those listed trial, second-line pharmacologic oral route of administration. If these
for these agents if they were to be options may be considered. These agents are initiated in the follicular
considered for use as contracep- second-line pharmacotherapies, phase of a menstrual cycle, women
tives.15 Women considering a preg- however, are associated with poten- may experience an initial 2- to
nancy in the near future may not tially more problematic short- and 3-week flare of symptoms due to a
want to use DMPA because of the long-term adverse effects.4 temporary increase in ovarian hor-
potential for a 9- to 10-month delay mones. If initiated during the luteal
in return to fertility. By contrast, re- GnRH agonists phase after ruling out pregnancy,
turn to fertility after discontinuation These agents are FDA approved for this flare is avoided, with suppres-
of the etonogestrel implant is gener- up to 12 months of use for treatment sion of hormonal levels and amen-
ally immediate. of ERPP.5 They bind to GnRH receptors orrhea occurring more quickly.21
Another POC option for relieving on the anterior pituitary, causing a Menopausal symptoms, including
ERPP is the levonorgestrel intrauter- down-regulation of the pituitary– hot flashes, mood swings, vaginal
ine system (LNG-IUS). A few small ovarian axis and profound but re- dryness, diminished sex drive, and
studies have shown LNG-IUS 52 mg versible hypoestrogenism (iatrogenic headaches, are common.
to have efficacy similar to that of menopause).4,5 Progressive endome- Bone loss occurs when GnRH
DMPA and gonadotropin-releasing trial atrophy and amenorrhea are the agonists are used for longer than 6
hormone (GnRH) agonists in reduc- result. Efficacy of GnRH agonists in months. Add-back therapy is used
ing ERPP.17–19 LNG suppresses endo- different doses, regimens, and routes to diminish the risk of bone loss.4,5
metrial proliferation, and amenorrhea of administration has been demon- Of note, women need not wait until
is common during use. Common strated in multiple clinical trials.20 6 months of GnRH agonist use to
adverse effects include irregular Overall, these agents have been found initiate add-back therapy, which has
spotting/bleeding, breast tenderness, to be more effective than placebo or not been shown to diminish the effi-
mood changes, and acne. Contrain- no treatment in relieving ERPP.20 cacy of pain relief but does increase
dications to use of LNG-IUS for treat- The most commonly used GnRH treatment cost.5 Add-back therapies
ment of ERPP are the same as those agonists are goserelin 3.6 mg SC include progestins, either alone or
if the product were being considered every 28 days, leuprolide 3.75 mg with an estrogen formulation or a
for use as a contraceptive.15 IM every month or 11.25 mg IM bisphosphonate. A daily calcium
every 3 months, or nafarelin 400 to supplement, usually elemental
Second-line treatments 800 mcg/day given as a nasal spray calcium 1,200 mg/day, is recom-
If first-line pharmacotherapies are twice daily. Disadvantages of GnRH mended.5 Use of GnRH agonists is
not effective after at least a 3-month agonists include cost and the non- contraindicated during pregnancy.
NPWomensHealthcare.com June 2020 Women’s Healthcare 9Nonpharmacologic approaches months.26 Adverse effects include
acne, weight gain, muscle cramps,
to therapy can be considered as
hirsutism, decreased breast size, and
deepening of the voice.27
needed. Referrals should be made to Aromatase inhibitors
Although not FDA approved for this
reproductive endocrinology specialists when indication, aromatase inhibitors (AIs)
such as oral anastrozole (1 mg/day)
fertility is a concern or when first- and oral letrozole (2.5 mg/day) are
used off label for severe ERPP refrac-
line pharmacotherapies are not tory to other pharmacotherapies.5
Overexpression of the aromatase
effective in reducing pain. enzyme is one of the main factors
responsible for estrogen synthesis in
endometrial lesions. AIs suppress ex-
GnRH antagonist hot flashes, headaches, nausea, in- traovarian estrogens, stopping endo-
In 2018, the FDA approved elagolix somnia, and mood changes, are also metrial lesion proliferation and pros-
sodium, the first GnRH antagonist dose dependent. Contraindications taglandin-mediated inflammation
indicated for moderate-to-severe to elagolix use are pregnancy and and pain.4,27 AIs may be an important
ERPP (dysmenorrhea, dyspareunia, hepatic dysfunction. option for women with endometri-
and noncyclic pelvic pain).22 Elagolix Elagolix has been directly com- osis whose symptoms persist after
is not associated with an initial flare of pared with other hormonal ther- menopause because most estrogens
symptoms because, as an antagonist, apies for ERPP. In a randomized are made outside the ovaries.28 In
it suppresses follicle-stimulating hor- controlled trial (RCT), elagolix 150 premenopausal women, AIs are often
mone (FSH), luteinizing hormone (LH), mg/day or 75 mg bid was similar to combined with progestins or GnRH
and estrogen effects immediately. DMPA in reducing ERPP, and both analogs to suppress both ovarian and
Elagolix is an oral tablet available treatments had minimal adverse ef- extraovarian estrogens.
in two dosages, 150 mg once daily fects on BMD.23 In the phase II Tulip Small studies in both premeno-
or 200 mg twice daily. The higher PETAL trial, elagolix 150 mg/day or pausal and postmenopausal women
dosage is more effective for all types 250 mg/day was similarly effective taking letrozole or anastrozole for
of ERPP but is associated with more as the GnRH agonist leuprorelin an average of 6 months have shown
bone loss. Efficacy of elagolix was acetate in reducing ERPP and had a decreased pain, reduction of extra-
demonstrated in two phase III trials, slightly less adverse effect on BMD.24 uterine endometrial growths, and im-
with a significant dose-dependent proved quality of life.29 A randomized
reduction in dysmenorrhea and Danazol 6-month clinical trial showed that
noncyclic pelvic pain by 3 months; This oral synthetic androgen was goserelin plus anastrozole increased
efficacy was sustained in an exten- approved for the treatment of en- pain-free intervals and decreased
sion trial at 12 months.22 The higher dometriosis more than 2 decades recurrence of pain in patients with se-
dosage was associated with a de- ago. Although shown to be effective, vere endometriosis.30 No significant
crease in dyspareunia. danazol is no longer commonly used bone loss was noted with this regi-
Elagolix is indicated for short- because of its androgenic effects and men. AIs are generally well tolerated,
term use (6 months for the higher the availability of other options.25 although musculoskeletal complaints
dosage and 24 months for the lower Danazol produces a high androgen such as arthralgias, joint stiffness, and
dosage) because of the risk of bone environment, suppresses FSH and LH, bone pain are fairly common and can
loss. Studies have shown that bone and lowers estrogen levels, causing lead to discontinuation. With long-
loss is dose dependent, with a sig- atrophy of endometrial implants and term use, AIs may increase risk of
nificant decrease in lumbar spine a resulting pseudomenopause. Da- osteoporosis and bone fracture.31 Be-
bone mineral density (BMD) by 6 nazol 400 to 800 mg/day is initiated cause AIs can reactivate ovarian cysts
months with the higher dosage.22 during menses, continued for 3 to and follicular function in reproduc-
Adverse effects of elagolix, including 6 months, and extended for up to 9 tive-age women, they are prescribed
10 June 2020 Women’s Healthcare NPWomensHealthcare.comwith hormonal contraceptives or Implications for practice and Gynecologists. Practice bulle-
tin number 114: management of
GnRH agonists to suppress follicular Nurse practitioners must be able to endometriosis. 2010; (reaffirmed
development.32 AIs are contraindi- inform women with ERPP about the 2018):1-14. acog.org/Clinical-Guid-
cated in women who are or may be- advantages and disadvantages of all ance-and-Publications/Prac-
come pregnant. the pharmacotherapeutic options tice-Bulletins/Committee-on-Prac-
so that they can make informed tice-Bulletins-Gynecology/
Management-of-Endometriosis.
Nonpharmacologic choices that best meet their needs.
treatments First-line pharmacotherapy for pain 6. Hediger ML, Hartnett HJ, Louis
GM. Association of endometriosis
Women with mild-to-moderate ERPP management can be initiated based
with body size and figure. Fertil
may benefit from nonpharmacologic on the presence of mild-to-moderate Steril. 2005;84(5):1366-1374.
approaches, alone or with pharma- symptoms and examination and ul- 7. American College of Obstetri-
cotherapy. In a small randomized trasound findings that rule out other cians and Gynecologists. ACOG
trial, use of a heating pad in patients potential causes. Nonpharmacologic committee opinion: dysmen-
with primary dysmenorrhea was as approaches to therapy can be consid- orrhea and endometriosis in
effective as ibuprofen 400 mg 3 times ered as needed. Referrals should be adolescence. Obstet Gynecol.
2018;132(6):e249-e257.
daily.33 Massage therapy just prior to made to reproductive endocrinology
menses onset may alleviate menstrual specialists when fertility is a concern 8. Pugsley Z, Ballard K. Management
of endometriosis in general prac-
pain associated with endometrio- or when first-line pharmacotherapies
tice: the pathway to diagnosis. Br J
sis.34 A small placebo-controlled trial are not effective in reducing pain. = Gen Pract. 2007;57(539):470-476.
demonstrated that oral melatonin
9. Barcellos MB, Lasmar B, Lasmar
significantly reduced pain and endo- Caitlin Henderson is a women’s R. Agreement between the preop-
metriosis-related dysmenorrhea.35 health nurse practitioner in a pri- erative findings and the operative
In vitro studies with endometrial vate ob/gyn practice in West Islip, diagnosis in patients with deep
cells have indicated that turmeric New York. Jennifer Hofmann is a endometriosis. Arch Gynecol Ob-
stet. 2016;293(4):845-850.
and omega-3 fatty acids may inhibit physician assistant and Associate
endometrial growths via reduction Clinical Professor at Pace Univer- 10. Marjoribanks J, Proctor M, Far-
quhar C, Derks RS. Nonsteroidal
of estradiol production.36 Dietary sity College of Health Professions
anti-inflammatory drugs for dys-
changes such as increasing con- in New York, New York. The au- menorrhoea. Cochrane Database
sumption of green vegetables and thors state that they do not have Systematic Rev. 2010;1:CD001751.
fruit and limiting ingestion of red a financial interest in or other 11. Brown J, Crawford TJ, Allen C, et
meats may decrease the risk of en- relationship with any commercial al. Nonsteroidal anti-inflammatory
dometriosis. Data on the effect of product named in this article. drugs for pain in women with en-
diet on the course of endometriosis, dometriosis. Cochrane Database
Syst Rev. 2017;1:CD004753.
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