Dysmenorrhea in adult females: Treatment

INTRODUCTION — Primary dysmenorrhea refers to the presence of recurrent, crampy, lower abdominal pain occurring during menses and the absence of demonstrable disease. Secondary dysmenorrhea is the occurrence of the same symptoms in response to clinically identifiable or suspected underlying pathology, such as endometriosis or adenomyosis. Treatment approaches must address the pain and, for secondary dysmenorrhea, the underlying etiology.

The management of patients with dysmenorrhea will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis of primary dysmenorrhea and dysmenorrhea in adolescents are discussed separately.

●(See "Dysmenorrhea in adult females: Clinical features and diagnosis".)

●(See "Primary dysmenorrhea in adolescents".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transmasculine and gender-expansive individuals.

TERMINOLOGY — For clinical purposes, dysmenorrhea is divided into two broad categories, primary and secondary:

●Primary dysmenorrhea refers to the presence of recurrent, crampy, lower abdominal pain that occurs during menses in the absence of demonstrable disease that could account for these symptoms. The diagnosis of primary dysmenorrhea, which is one of exclusion, is made more often in adolescents and young adult females.

●Secondary dysmenorrhea has the same pain symptoms but occurs in individuals with a disorder that could account for their symptoms, such as endometriosis, adenomyosis, or uterine fibroids. Patients with these diseases often have clinical features that separate them from primary dysmenorrhea, including a large uterus, pain with intercourse, and resistance to effective treatments.

OUR APPROACH — The goal of treatment is to provide adequate relief of pain. At a minimum, pain relief should be sufficient to allow patients to perform most, if not all, of their usual activities and to reduce the productivity loss commonly associated with dysmenorrhea [1]. Treatment of primary dysmenorrhea can be initiated empirically (algorithm 1). Laboratory tests, imaging studies, and/or laparoscopy are not required to definitively exclude causes of secondary dysmenorrhea when a detailed history and physical examination strongly support the diagnosis, particularly in adolescents. Relief of symptoms with standard treatments, as reviewed below, further supports the diagnosis of primary dysmenorrhea. If symptoms do not sufficiently respond to standard treatments, we begin an evaluation for causes of secondary dysmenorrhea. (See "Dysmenorrhea in adult females: Clinical features and diagnosis", section on 'Diagnostic evaluation'.)

●Baseline interventions – General measures for management include patient education and reassurance. Treatment is supportive and should be guided by individual needs, as the severity of pain and degree of limitation of activity vary widely among individuals with dysmenorrhea. Symptom grading systems exist but are often limited to research settings (table 1). The initial approach includes a discussion of nonpharmacologic interventions that can be helpful, such as exercise and application of a heat pack to the lower abdomen (algorithm 1). (See 'Baseline interventions' below.)

●First-tier treatment – For individuals who do not have adequate relief with baseline interventions or who desire immediate pharmacologic therapy, first-line treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol), and/or hormonal contraception (algorithm 1). Hormonal contraception includes combined estrogen-progestin products (oral pills, transdermal patches, and vaginal rings) and progestin-only options (implant, injection, intrauterine device, and oral pills). Choice of treatment order depends on the clinical needs and preferences of the patient. For those with primary dysmenorrhea desiring contraception, hormonal contraception is a logical initial choice. Initiating hormonal contraception may also be appropriate for persons who do not need contraception (eg, they are not sexually active with a male partner) and do not currently wish to conceive. For individuals who prefer not to use hormonal treatment, NSAIDs or acetaminophen are a logical first choice. Treatment typically begins just prior to or with the onset of menses and continues for two to three days. Treatment duration depends on the duration of the patient's menses and symptom pattern. Some patients may benefit from combinations of treatments. Patient-specific factors, such as personal treatment goals and the cost and convenience of various treatments, help guide treatment selection. (See 'First-tier' below.)

We begin the initial treatment for two to three months and then reassess the patient's symptoms.

•For patients whose symptoms improve somewhat but still have pain, we discuss adding an additional treatment from the first-tier category and continuing the initial treatment (ie, combination treatment). As an example, for a patient whose symptoms improve with NSAID therapy but not enough to resume the usual range of activities, we offer additional treatment with a hormonal contraceptive. Treatment with both hormonal contraception and NSAIDs may be effective in those who remain symptomatic on either therapy alone.

•For patients with no or minimal response to treatment after two or three months, we offer a treatment change to the other first-tier options and stop the initial intervention. In addition, reevaluation of the original diagnosis is always indicated when therapies do not result in the anticipated level of response.

We observe patients on combination therapy or treatment change for up to an additional three months. Patients who have adequate symptom response continue on the effective therapy. Patients who do not have an adequate response are then reevaluated for underlying causes of their dysmenorrhea (ie, secondary dysmenorrhea).

●Reevaluate for underlying causes of dysmenorrhea – Patients who do not achieve adequate pain relief after three to six months of treatment with NSAIDs and/or hormonal contraceptives, either alone or in combination, may have secondary dysmenorrhea (ie, dysmenorrhea related to underlying pathology) (table 2). Clinical features suggesting secondary dysmenorrhea include persistent symptoms resistant to standard treatment, missing work or school, and multiple visits to the emergency department or urgent care clinics for pain with menses. We repeat a targeted diagnostic evaluation that is guided by the unique history and symptoms of each patient. We particularly focus our evaluation on common causes of secondary dysmenorrhea, including endometriosis and adenomyosis.

•(See "Dysmenorrhea in adult females: Clinical features and diagnosis", section on 'Diagnostic evaluation'.)

•(See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

•(See "Uterine adenomyosis".)

●Second-tier treatment – For patients with continued menstrual pain despite the above treatments, we next offer a trial of transcutaneous electrical nerve stimulation and/or empiric treatment with gonadotropin-releasing hormone analogs, including agonists (eg, leuprolide acetate, nafarelin, goserelin) and antagonists (eg, elagolix). These medications have proven efficacy for treatment of endometriosis-related dysmenorrhea. Their role in patients without endometriosis is not known. However, the time required for treatment, side effects, and cost may limit use of these therapeutic options. Patients who decline these treatments or who do not improve then generally proceed with laparoscopy.

•(See 'Transcutaneous electrical nerve stimulation' below.)

•(See 'Empiric GnRH analog therapy' below.)

●Role of laparoscopy – Patients who do not respond to the above interventions have a high likelihood of pelvic pathology. For this reason, we offer diagnostic laparoscopy for individuals with dysmenorrhea who have not had adequate relief after three to six months of NSAIDs and/or hormonal contraception. The most common diagnosis is endometriosis. (See 'Role of laparoscopy' below.)

●Refractory dysmenorrhea – Despite the above treatments, a minority of patients will continue to have dysmenorrhea that limits their function. For patients whose dysmenorrhea appears to be related to heavy menstrual bleeding and who do not desire future childbearing, endometrial ablation is an option. For patients who have exhausted all treatment options and have completed their childbearing, hysterectomy is the definitive treatment. We do not advise nerve transection procedures for treatment of dysmenorrhea, although there may be a role in select patients with chronic midline pelvic pain.

•(See 'Surgery for refractory dysmenorrhea' below.)

•(See 'Ineffective or unproven treatments' below.)

●Inclusion of supportive therapies – Supportive therapies, such as behavioral counseling, complementary or alternative medicine, or dietary changes, can be started at any time by interested patients and used in conjunction with the treatments above. While the available supporting data are weak, the risks appear to be low. (See 'Supportive therapies' below.)

BASELINE INTERVENTIONS — We begin with a discussion of self-care approaches to pain relief, especially for those who want to avoid drug therapy. We discuss the approaches in the order below.

Exercise — The body of evidence supports a role for exercise in the treatment of dysmenorrhea. However, the optimal type, duration, and frequency of exercise to relieve symptoms is not known. A meta-analysis of 11 trials reported reduced pain intensity and duration for exercise versus any nonexercise comparator, although result heterogeneity was high [2]. Subsequent small trials have also reported reduced pain intensity and duration with exercise compared with usual care [3-8]. One pilot study reported exercise-mediated increases in progesterone and reductions in pain mediators as potential mechanisms for the response [9]. As there are multiple health benefits to exercise and the risk of harm is low, increasing physical activity is a reasonable approach to reduce dysmenorrhea. (See "The benefits and risks of aerobic exercise".)

Heat — In randomized trials, application of heat to the lower abdomen was effective for relief of dysmenorrhea [10,11]. Heat had similar efficacy as ibuprofen [10,12] and was more effective than acetaminophen [11]. Most individuals find applying heat more cumbersome than taking oral medications, but it has no side effects. Heat therapy may improve the efficacy of other treatments [13].

FIRST-TIER — Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol), and hormonal contraceptives are the mainstays of drug therapy. No randomized trials have compared the efficacy of NSAIDs versus hormonal contraception for treatment of primary dysmenorrhea. If treatment with one of these agents fails after two or three months, we advise a course of treatment with the other. Treatment with both hormonal contraception and NSAIDs may be effective in those who remain symptomatic on either drug alone. In addition, reevaluation of the original diagnosis is always indicated when therapies do not result in the anticipated level of response. (See 'Our approach' above.)

Nonhormonal therapy — For patients who do not desire hormonal contraception or prefer/need to avoid hormonal therapy, we suggest treatment with NSAIDs. Acetaminophen is an alternative treatment for patients who cannot tolerate NSAIDs.

Nonsteroidal anti-inflammatory drugs — NSAIDs more effectively treat dysmenorrhea-related pain compared with placebo. A meta-analysis including 80 trials reported that NSAIDs were more effective than placebo for patients with primary dysmenorrhea (odds ratio [OR] 4.37, 95% CI 3.76-5.09, 35 trials for comparison) [14]. However, NSAIDs were also associated with a 30 percent increased likelihood of adverse effects overall (OR 1.29, 95% CI 1.11-1.51, 25 trials) and a nearly 60 percent increased risk of gastrointestinal side effects (OR 1.58, 95% CI 1.12-2.23, 14 trials). Most of the adverse effects were mild.

●Choice of agent – Although the above meta-analysis and other studies did not report efficacy differences across nonspecific NSAIDs [14-17], others suggest that differences exist and that fenamates (mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamate, bromfenac) may have slightly better efficacy than the phenylpropionic acid derivatives (ibuprofen, naproxen) [18,19]. Both fenamates and phenylpropionic acid derivatives inhibit prostaglandin synthesis, but fenamates also block prostaglandin action, which may account for their enhanced effectiveness in some studies. At least one network meta-analysis has reported that fenamates and phenylpropionic acid derivatives provided better pain relief compared with aspirin [20]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

As there are insufficient data on which to base a recommendation for one class of agents or the other, we take the following approach to NSAID treatment, although other treatment regimens are reasonable:

•We begin treatment with a phenylpropionic acid derivative prescribed at the upper end of the dose range (table 3). These drugs are relatively inexpensive, available without prescription, easy to dose, and of demonstrated efficacy. We prescribe ibuprofen 400 to 600 mg every four to six hours or 800 mg every eight hours to a maximum dose of 2400 mg per day, starting with the onset of symptoms or menses, and continue this dose for two or three days based on the patient's usual symptom pattern. In the above meta-analysis [14], some of the included studies did not indicate when participants initiated NSAIDs, others stated "at onset of pain," while others specified "at onset of symptoms." The US Food and Drug Administration packaging insert for ibuprofen indicates the drug should be started "for the treatment of dysmenorrhea, beginning with the earliest onset of such pain" [21].

•For individuals whose symptoms do not adequately improve with two to three months of phenylpropionic acid treatment, we next offer a fenamate (eg, mefenamic acid 500 mg initially followed by 250 mg every six hours, with treatment typically limited to three days) (table 3).

Since NSAIDs are given for only a few days to young, generally healthy persons, adverse effects tend to be less frequent than in other patient populations. General considerations regarding therapeutic use, drug interactions, and toxicities of NSAIDs are discussed in detail separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects".)

●COX-2 selective NSAIDs (coxibs) – The only COX-2 selective NSAID specifically studied and indicated for treatment of (primary) dysmenorrhea is celecoxib, although others are available. These drugs are more expensive than nonspecific NSAIDs but may be useful in individuals who are at high risk for NSAID-related gastroduodenal toxicity. However, most of these agents have either been withdrawn from the market or issued with black box warnings regarding the risk of serious adverse events. Given these risks and the availability of safe and effective alternatives (nonspecific NSAIDs, as discussed above), we do not use COX-2 inhibitors for treatment of primary dysmenorrhea. (See "Overview of COX-2 selective NSAIDs" and "NSAIDs: Adverse cardiovascular effects".)

●Potential delay of ovulation – Because prostaglandins play an important role in ovulation, NSAIDs, particularly COX-2 inhibitors, can prevent or delay this process [22-24]. In fact, the negative effect of COX-2 inhibitors on ovulation is the basis of studies of these agents as potential emergency contraceptives [25]. Clinical studies examining the effects of various NSAIDs in normally cycling subjects have demonstrated mixed effects on ovulation [26-30].

Individuals taking NSAIDs and attempting to conceive can generally be reassured that NSAID therapy is unlikely to delay ovulation because these agents are only used at the time of menstruation. However, if a patient experiences difficulty conceiving, we suggest avoiding these drugs or reducing the dose, if possible, though the effect of such reduction is unproven [31,32].

Acetaminophen (paracetamol) — Acetaminophen is a reasonable alternative for patients with medical contraindications to or intolerance of NSAIDs who desire pharmacotherapy for pain relief. Although the above meta-analysis reported NSAID treatment appeared more effective at reducing pain than acetaminophen based on data from three trials (OR 1.89, 95% CI 1.05-3.43), acetaminophen does not typically have adverse gastrointestinal side effects. A meta-analysis of self-care strategies used by young women (under age 25) with dysmenorrhea reported that nearly one-third used acetaminophen to treat their pain, but nearly one-half reported inadequate pain relief [33]. Studies evaluating acetaminophen in combination with either caffeine or pamabrom (a short-acting diuretic) have reported reduced pain [34,35]. We reserve acetaminophen trials for patients with NSAID intolerance who also prefer to avoid hormonal contraception.

Hormonal contraception — For people with dysmenorrhea who either desire contraception or for whom use of a contraceptive is acceptable, we suggest treatment with an estrogen-progestin hormonal contraceptive (eg, combined estrogen-progestin oral pills, transdermal patches, or vaginal rings) or placement of a levonorgestrel-releasing intrauterine device as a first-line option. The choice of method is ultimately determined by the patient and based on preferences for dosing, cycle control, cost, availability, and side effects, among other variables. (See "Contraception: Counseling and selection".)

Estrogen-progestin methods — Estrogen-progestin contraceptives contain synthetic progestins that suppress ovulation and cause the endometrium to become thin over time. The thin endometrium contains relatively small amounts of arachidonic acid, the substrate for most prostaglandin synthesis. As a result of these changes in the endometrium, estrogen-progestin contraceptives reduce both uterine bleeding flow and uterine contractions occurring during flow, thereby decreasing dysmenorrhea. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

●Oral pills – Although limitations of contraceptive pill studies have included small sample sizes, limited comparative data, and inclusion of multiple treatment regimens, the body of evidence suggests that any combination oral estrogen-progestin contraceptive pill is likely to reduce dysmenorrhea. A meta-analysis of trials comparing estrogen-progestin contraceptive pills with placebo reported treatment benefit (pooled OR 2.01, 95% CI 1.32-3.08, seven trials) [36]. The meta-analysis also concluded pain relief was similar for pills with estrogen doses ≤35 mcg and >35 mcg, and there was no clear difference in efficacy among the different pill preparations. Lower dose formulations (eg, 20 mcg of ethinyl estradiol) also appear to be effective at reducing pain [37-42]. While trials have reported better relief of menstrual symptoms with extended or continuous dosing compared with cyclic administration, all regimens appear to be effective for symptom relief [43-45]. For patients in whom conventional cyclic dosing (21 days of medication/7 days of placebo) of oral contraceptive formulation does not provide sufficient relief of dysmenorrhea, it is reasonable to change to a formulation with a reduced hormone-free interval (eg, a 24/4 formulation) or an extended cycle formulation. Cycle selection is ultimately determined by patient preference. At least one consensus guideline advises pill use to reduce dysmenorrhea [46].

•(See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

•(See "Hormonal contraception for menstrual suppression", section on 'Combined estrogen-progestin methods'.)

●Vaginal rings and transdermal patches – As transdermal and vaginal estrogen-progestin contraceptives are newer than oral contraceptives, few trials have evaluated their efficacy for treatment of primary dysmenorrhea or compared them with other therapies. The endometrial effects of estrogen-progestin contraceptives are similar regardless of the method of delivery; therefore, the route of administration should not significantly affect efficacy. (See "Contraception: Hormonal contraceptive vaginal rings" and "Contraception: Transdermal contraceptive patches".)

•Ring versus pill – A review of 12 randomized trials comparing the contraceptive vaginal ring containing etonogestrel with oral contraceptives concluded both methods had a similar favorable impact on dysmenorrhea [47]. The proportion of participants reporting moderate or severe dysmenorrhea decreased similarly for both groups (contraceptive ring: 17.4 to 5.9 percent; oral contraception users: 19.0 to 6.4 percent) [48].

•Patch versus pill – In a randomized trial designed to evaluate contraceptive efficacy and cycle control in norelgestromin/ethinyl estradiol contraceptive patch and oral contraceptive pill users, dysmenorrhea was slightly more common among women assigned to the patch (13.3 versus 9.6 percent) [48]. Although statistically significant (p = 0.04), this difference may have been due to chance.

Progestin-only methods — Since the progestin component of estrogen-progestin contraceptives induces the endometrial atrophy that leads to relief of dysmenorrhea, progestin-only contraceptives may be an effective treatment, but they have not been studied as extensively as estrogen-progestin contraceptives. Some side effects, particularly irregular bleeding, are more common with progestin-only methods than with estrogen-progestin contraceptives. An advantage of progestin-only contraceptives is that they can be safely used by individuals for whom contraceptive doses of estrogen are contraindicated. A disadvantage is that norethindrone progestin-only methods do not inhibit ovulation as consistently as estrogen-progestin contraceptives, which may be important when used for treatment of dysmenorrhea. While all of the methods below have some efficacy data for reducing dysmenorrhea, there are no comparative studies. Thus, selection of a treatment is based on patient preferences. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates' and "Contraception: Progestin-only pills (POPs)".)

●Levonorgestrel (LNG)-releasing intrauterine devices (IUDs) – Use of the 20 mcg LNG-releasing IUD is associated with reductions in dysmenorrhea, in part because of the approximately 20 percent amenorrhea rate after one year of use [49-55]. The one-year amenorrhea rates are lower with the lower dose LNG-releasing IUDs (12 percent of LNG 19.5 users and 6 percent of LNG 14 users) [56-58]. (See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

A systematic review reported that LNG IUDs have an efficacy similar to oral estrogen-progestin pills for relief of dysmenorrhea [52]. Other data come from studies of surrogate populations. In a randomized trial of women with pelvic pain related to endometriosis, the 20 mcg LNG IUD was as effective as depot gonadotropin-releasing hormone agonist for control of pelvic pain [59]. A noncomparative study of 29 symptomatic women with magnetic resonance imaging-diagnosed adenomyosis reported that placement of a 20 mcg LNG significantly reduced pain scores at three and six months [60].

By contrast, copper T380A IUD users experience increased dysmenorrhea, which is a leading cause of discontinuation during the first year of use. (See "Intrauterine contraception: Candidates and device selection".)

●Implantable contraception – In a large three-year Chilean clinical trial assessing the safety and efficacy of the single-rod etonogestrel-releasing contraceptive, over three-quarters of participants who reported primary dysmenorrhea at baseline noted an improvement at the end of treatment, while only 4 percent reported new or worsened dysmenorrhea [61]. In another trial, the single-rod etonogestrel-releasing contraceptive was associated with a 68 percent reduction of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia in women with histologically proven endometriosis [62]. In an analysis of 11 clinical trials of women (n = 923) using the contraceptive implant, complete resolution was achieved in more than three-fourths of implant recipients who reported dysmenorrhea prior to implant placement [63]. (See "Contraception: Etonogestrel implant".)

●Progestin-only pills (POPs) – POPs available in the United States include norethindrone 0.35 mg tablets and drospirenone 4 mg tablets. Although studies support progestin-only treatment for patients with secondary dysmenorrhea related to endometriosis, its efficacy for treating primary dysmenorrhea is less clear [64-67]. A major limitation is the unscheduled bleeding associated with POPs [68].

Treatment with oral norethindrone acetate 5 mg tablets represents a high-dose progestin-only option that has a low rate of unscheduled bleeding. However, this medication is not labeled for contraception. A trial randomly assigned a total of 38 patients with primary dysmenorrhea to continuous norethindrone acetate 5 mg tablets or estrogen-progestin oral contraceptive pills (cyclic dosing fashion) [67]. At six months of follow-up, the reduction in dysmenorrhea was similar between the two groups. One concern with use of higher doses of norethindrone acetate (2.5 to 10 mg) is a possible increased risk of deep vein thrombosis (DVT) [69]. Potential mechanisms for elevated DVT risk include that norethindrone and norethindrone acetate are converted to ethinyl estradiol in small quantities and that norethindrone acetate may impact gene expression of coagulation factors [70,71]. Thus, active thromboembolism is listed as a relative contraindication to norethindrone acetate use [72]. (See "Contraception: Progestin-only pills (POPs)".)

●Injectable contraception – Limited observational data suggest injectable depot medroxyprogesterone acetate is associated with reductions in dysmenorrhea [73]. One likely mechanism is the 50 percent amenorrhea rate that occurs after one year of use as a result of endometrial atrophy [74]. However, return of fertility may be delayed after discontinuation, so those who may want to become pregnant within the next one or two years are advised to choose a different method. (See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

SECOND-TIER

Transcutaneous electrical nerve stimulation — Transcutaneous electrical nerve stimulation (TENS) is a reasonable next step for patients with continued pain despite the interventions above. This nonpharmacologic treatment can be used in addition to nonhormonal and/or hormonal therapies. This modality is also an alternative for patients who cannot or prefer not to use medications. One minimally invasive TENS option is percutaneous tibial nerve stimulation (PTNS). The major limitation of PTNS treatment is the need for weekly treatments for 12 weeks in a row. The patient completes the treatment course and then symptoms are reassessed. Patients with adequate pain improvement then continue any treatments that they were previously using. TENS treatment can be repeated if symptoms recur. Patients who do not improve with TENS proceed to the next treatment option. (See "Chronic pelvic pain in adult females: Treatment".)

In a meta-analysis comparing high-frequency TENS with placebo for primary dysmenorrhea, high-frequency TENS more effectively reduced pain (odds ratio [OR] 7.2, 95% CI 3.1-16.5, two trials, 106 women) [75]. However, pain relief from low-frequency TENS was similar to that of placebo (OR 1.76, 95% CI 0.60-5.09, two trials, 63 women). A subsequent trial of 134 patients with primary dysmenorrhea that compared TENS with sham TENS reported greater pain relief and duration of pain relief, reduction of ibuprofen with active TENS, but similar outcomes in quality of life [76]. The degree of pain relief obtained with TENS alone is less than that from drugs; however, some patients may be able to lower their analgesic dose with combined therapy. TENS may also be combined with topical heat therapy with good effect [77].

TENS is hypothesized to have two effects: (1) it raises the threshold for pain signals from uterine hypoxia and hypercontractility by sending a volley of afferent impulses through the large diameter sensory fibers of the same nerve root, resulting in lower perception of painful uterine signals, and (2) it stimulates release of endorphins from the peripheral nerves and the spinal cord [78]. Intrauterine pressure studies indicate that TENS therapy had no effect on uterine contractile activity [79].

Empiric GnRH analog therapy — While we generally base our decision for gonadotropin-releasing hormone (GnRH) analog treatment on the findings at laparoscopy, there is a role for empiric treatment, including:

●Patients with persistent dysmenorrhea who desire to avoid surgery – One option is to make a presumptive diagnosis of endometriosis and offer these women treatment with a GnRH analog. GnRH agonists include nafarelin (200 mcg intranasal spray twice per day) or leuprolide acetate depot (3.75 mg intramuscularly every four weeks) [80]. However, treatment with these agents is often limited by side effects. An alternative option is treatment with a GnRH antagonist, such as elagolix, which is orally dosed. If the pain significantly improves or resolves with either agonist or antagonist therapy, then endometriosis is likely, although not confirmed. (See "Endometriosis: Treatment of pelvic pain", section on 'Agonists'.)

●Patients with persistent pain and negative laparoscopy – If laparoscopy is negative and the patient has previously failed both hormonal contraception and nonsteroidal anti-inflammatory drugs, we would try a three-month course of a GnRH agonist, such as nafarelin or leuprolide, since endometriosis may have been missed. Even in the hands of experienced laparoscopists, an accurate diagnosis of endometriosis can be difficult since the disease is often microscopic and presents visually with a variety of atypical lesions. For patients who do not tolerate or desire GnRH agonist treatment, use of a GnRH antagonist is a reasonable option, although supporting data are limited as it is a newer treatment. (See "Endometriosis: Treatment of pelvic pain", section on 'Gonadotropin-releasing hormone (GnRH) analogs'.)

Limitations of GnRH analog treatment include menopause-like side effects, cost, and loss of bone density with long-term use. For these reasons, we generally reserve GnRH agonist/antagonist treatment for individuals with confirmed endometriosis. Alternatively, and if not already tried, continuous or extended-cycle estrogen-progestin contraception, a levonorgestrel-releasing intrauterine device, continuous norethindrone acetate tablets, or depot medroxyprogesterone acetate can be used in this setting. These agents are more affordable and safer over long-term use than GnRH analogs. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)

ROLE OF LAPAROSCOPY — We offer diagnostic laparoscopy for individuals with dysmenorrhea who have not had adequate relief after three to six months of nonsteroidal anti-inflammatory drugs and/or hormonal contraception [81]. Studies have reported that 70 to 80 percent of women with persistent pelvic pain are diagnosed with endometriosis at the time of laparoscopy [80,82-86]. However, the role and timing of laparoscopy depends on patient and clinician preference. As noted above, some patients strongly wish to avoid surgery, in which case empiric treatment with a gonadotropin-releasing hormone agonist/antagonist is a reasonable alternative. (See 'Empiric GnRH analog therapy' above.)

SURGERY FOR REFRACTORY DYSMENORRHEA

Endometrial ablation — Endometrial ablation appears to be helpful for select patients not desiring future childbearing whose dysmenorrhea is related to heavy menstrual bleeding. In a retrospective cohort study of 144 patients who underwent endometrial ablation, nearly one-half (48/100) of the women with preoperative dysmenorrhea had resolution of their symptoms after ablation [87]. Patients who had a reduction in menstrual flow following ablation were more likely to report resolution of their dysmenorrhea.

●(See "Overview of endometrial ablation".)

●(See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

Hysterectomy — We reserve hysterectomy for patients who have completed childbearing and have inadequate response to the above therapies. (See "Hysterectomy (benign indications): Selection of surgical route".)

SUPPORTIVE THERAPIES — While behavioral counseling and diet/dietary supplements show some promise for reducing dysmenorrhea, the supporting evidence is weak to limited. Interested patients are welcome to add these approaches to their treatment regimens, but safety and efficacy are inadequately studied.

Behavioral counseling — Behavioral counseling teaches patients strategies to modify the way they think about their pain (eg, desensitization-based procedures, hypnotherapy, imagery, coping strategies) and attempts to modify their response to pain (eg, biofeedback, electromyographic training, Lamaze exercises, relaxation training). There is no high-quality evidence to support or refute use of these modalities; two different reviews concluded some patients may be helped by them [88,89]. We find behavioral counseling a helpful adjunct to exercise and pharmacologic therapy in motivated patients.

Physiotherapy treatment — Physiotherapy and activity-based therapies may be helpful and carry little risk. A meta-analysis evaluating use of isometric exercises, massage therapy, yoga, electrotherapy, connective tissue manipulation, stretching, kinesio tape, progressive relaxation exercises, and aerobic dance found some support for the use of these modalities but noted that the evidence was of low quality [90]. A similar literature review of therapeutic taping reported some improvement in anxiety but limited other benefits [91]. A randomized controlled trial of connective tissue manipulation (CTM) in primary dysmenorrhea reported a reduction in the perception of pain but no reduction in the use of other analgesics [92]. Given the paucity of high-quality data, we see these modalities as supplemental therapies for interested patients.

Complementary or alternative medicine — There is limited evidence from controlled trials to support the use of complementary or alternative medicine for treatment of dysmenorrhea. However, as the risk from these interventions is also low, patients who wish to use them may reasonably do so.

●Acupuncture or acupressure – Although multiple studies of acupuncture for treatment of dysmenorrhea have been published, these studies are generally of low quality and vary widely in design. As a result of study heterogeneity, a 2016 meta-analysis of 42 trials on acupuncture or acupressure was unable to determine if acupuncture or acupressure was effective in treating primary dysmenorrhea [93]. A 2018 meta-analysis of 49 trials concluded that, while the available data were mostly of low quality, acupuncture might reduce dysmenorrhea symptoms compared with no treatment or nonsteroidal anti-inflammatory drug therapy [94]. A separate trial including 221 women comparing smartphone app acupressure self-treatment with usual care reported reduced menstrual pain with self-acupressure and noted an improved response over time (three to six months) [95]. Small but significant improvements were noted in the worst pain intensity, number of days with pain, and proportion of patients using pain medication. Study limitations include an open-label design and lack of an active comparator group. Nonetheless, this trial highlights the benefits of studying symptom response over more than one cycle in order to optimally assess treatment efficacy. A trial that compared dry needling of the rectus abdominis with sham needling or no treatment reported greater reductions in reported pain and medication use by patients who received the active treatment [96]. One meta-analysis noted the absence of safety data in most of these studies, concluding that there is not enough evidence to support the safety of simple needling in the treatment of primary dysmenorrhea [97].

●Other – A systematic review of four trials of high-velocity, low-amplitude spinal manipulation reported the technique was no more effective than sham manipulation for the treatment of primary dysmenorrhea, although it was possibly more effective than no treatment [98].

One small trial reported Japanese herbal combinations were more effective for reducing pain than placebo [99]. In a systematic review of 39 randomized trials of Chinese herbal medicine for treatment of primary dysmenorrhea, this approach appeared to be promising compared with other therapies, but no firm conclusions could be made due to poor methodologic quality of the available trials [100]. A randomized controlled parallel-group study demonstrated comparable pain response for acupressure and motor imagery-focused pelvic floor exercise, but the sample size and the clinical effects reported were small [101].

Diet and vitamins — A variety of dietary changes and vitamin therapies have been reported to reduce the severity of menstrual pain, but data are limited to a few small studies. Although the limited available data appear promising, we would like to see confirmatory data from additional trials before suggesting these interventions for our patients [102]. Interventions that have been associated with some reduction in dysmenorrhea include:

●Low fat vegetarian diet [103].

●Increased dairy intake [104].

●Vitamin E (500 units per day or 200 units twice per day, beginning two days before menses and continuing through the first three days of bleeding) [105,106].

●Vitamin B1 (100 mg daily), vitamin B6 (200 mg daily), and fish oil supplement (1080 mg eicosapentaenoic acid, 720 mg docosahexaenoic acid, and 1.5 mg vitamin E) were each more effective for reducing pain than placebo [99].

●A single large dose of vitamin D3 (oral, 300,000 international units/1 mL) given five days prior to the expected first day of the menstrual cycle, although the safety of this approach is unclear [107,108].

●Consumption of 750 to 2000 mg of ginger powder on days 1 to 3 of the menstrual cycle [109-112].

●Dietary supplementation with omega-3 polyunsaturated fatty acids has shown limited effects but a paradoxical reduction in effect with increasing doses and patient age [113].

LIMITATIONS OF AVAILABLE DATA — A placebo effect is particularly strong in primary dysmenorrhea trials, especially in the first month of treatment. However, the effects of placebo treatment appear to fade quickly. This was illustrated in a study in which placebo therapy was associated with self-reported improvement in symptoms in the first, second, third, and fourth months of treatment in 84, 29, 16, and 10 percent of women, respectively [114]. By comparison, active treatment with nonsteroidal anti-inflammatory drugs produced an 80 to 86 percent response rate that was maintained throughout the four months of treatment. These results underscore that, optimally, treatment of primary dysmenorrhea is informed by prospective, double-blind trials in which treatment is administered and tracked over several cycles.

INEFFECTIVE OR UNPROVEN TREATMENTS

●Nerve transection procedures – There is insufficient evidence to recommend nerve transection procedures, including laparoscopic uterine nerve ablation and presacral neurectomy, for relief of dysmenorrhea [115-117]. There may be a role for presacral neurectomy in patients with chronic midline pelvic pain associated with endometriosis [118]. The use of these procedures for patients with endometriosis and chronic pelvic pain is described elsewhere.

•(See "Endometriosis: Treatment of pelvic pain", section on 'Nerve transection'.)

•(See "Chronic pelvic pain in adult females: Treatment", section on 'When to perform additional surgical procedures aimed to reduce pain'.)

●Aromatase inhibitors – While there are some data supporting use of aromatase inhibitors (AI) in patients with secondary dysmenorrhea and pelvic pain related to endometriosis, these agents are not typically used for patients with primary dysmenorrhea. AI treatment is generally reserved for those with severe, refractory endometriosis-related pain [119,120]. (See "Endometriosis: Treatment of pelvic pain", section on 'Aromatase inhibitors'.)

●Tocolytics – Primary dysmenorrhea is caused by excessive uterine muscle contractions. Thus, agents that block uterine contractility (ie, tocolytics) may be effective in the treatment of this disorder. Nitric oxide, nitroglycerin, and calcium channel blockers all have tocolytic effects and are under investigation as potential therapies of dysmenorrhea. We do not currently use any of these drugs for treatment of primary dysmenorrhea.

•Nitroglycerin (glyceryl trinitrate) – A multinational, double-blind, placebo-controlled, randomized crossover trial demonstrated that nitroglycerin (glyceryl trinitrate) patches (0.1 mg per hour) were effective for reduction of dysmenorrhea [121]. However, in another trial that compared nitroglycerin (glyceryl trinitrate) with a nonsteroidal anti-inflammatory drug (NSAID; diclofenac 50 mg daily) in the treatment of primary dysmenorrhea, nitroglycerin (glyceryl trinitrate) was less effective than the NSAID and was associated with more side effects, particularly headache [122]. Although nitroglycerin (glyceryl trinitrate) is effective in reducing pain, low tolerability limits its use [123].

•Nifedipine – Nifedipine (single oral dose of 20 to 40 mg) has been documented to reduce the intensity of uterine contractions [124] and relieve pain in individuals with primary dysmenorrhea, although supporting data are limited by small numbers of study participants [124-127]. In one study including 12 women with severe dysmenorrhea, nifedipine (single oral dose of 30 mg) relieved dysmenorrhea within 60 minutes in the majority of women treated [125]. In another study, nifedipine given to 40 women with dysmenorrhea resulted in moderate to good pain reduction in 36 patients but was associated with a moderate rate of side effects (facial flushing, tachycardia, headache) [126]. Serious cardiovascular events have occurred when short-acting calcium channel blockers were given to patients with hypertension. (See "Major side effects and safety of calcium channel blockers".)

•Magnesium – Three small randomized trials found that magnesium was more effective than placebo for relief of dysmenorrhea and was well-tolerated [99]. However, the small size of the trials, high dropout rates, and varying designs precluded a definite recommendation for use of magnesium or the optimum dose or regimen.

●Phosphodiesterase inhibitors – By inhibiting phosphodiesterase, sildenafil enhances the vasodilatory effects of nitric oxide, facilitating myometrial blood flow, and thus reducing primary dysmenorrhea. Oral medications that enhance nitric oxide's relaxation of myometrial cells can relieve prostaglandin-associated menstrual pain, but side effects associated with this route of administration have precluded clinical use for primary dysmenorrhea. Vaginal administration has been investigated. In a small randomized, double-blind trial, the efficacy of a vaginal preparation of sildenafil citrate (100 mg single dose) was assessed in 62 women with primary dysmenorrhea. Vaginal sildenafil reduced primary dysmenorrhea more than placebo. However, the study was not able to meet its recruitment goals, and accordingly, the findings were not conclusive [128].

●Anticholinergic agents – Scopolamine (hyoscine) butylbromide and related drugs that relax smooth muscle through muscarinic receptors can be used to treat dysmenorrhea [129,130]. However, supporting data are sparse, and medication use is often limited by side effects, which typically include dry mouth, constipation, and dizziness [131].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dysmenorrhea".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Painful periods (The Basics)")

●Beyond the Basics topics (see "Patient education: Painful menstrual periods (dysmenorrhea) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Treatment goals – The goal of treatment is to provide adequate relief of pain. At a minimum, pain relief should be sufficient to allow patients to perform most, if not all, of their usual activities. Treatment of primary dysmenorrhea can be initiated empirically. (See 'Our approach' above.)

●Nonpharmacologic interventions – Low-risk baseline, nonpharmacologic interventions with documented efficacy include exercise and heat application (algorithm 1). As these are low cost and low risk, we discuss these treatments with all dysmenorrhea patients. (See 'Baseline interventions' above.)

●First tier medication therapy – For patients with inadequate response to baseline interventions, nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal contraceptives are the mainstays of therapy (algorithm 1). There is no evidence favoring one of these medication classes over the other. If treatment with one of the modalities fails or is inadequate after three months, we try a course of treatment with the other modality. Treatment with both NSAIDs and hormonal contraceptives may be effective in individuals who remain symptomatic on either drug alone. (See 'First-tier' above.)

•Nonsteroidal anti-inflammatory drugs (NSAIDs) – For individuals who desire analgesic medications for treatment of dysmenorrhea, we suggest NSAIDs for first-line therapy (Grade 2C). NSAID therapy is more effective than placebo and acetaminophen and is generally well tolerated. We start with a phenylpropionic acid derivative, such as ibuprofen, at the upper end of the dose range (400 to 600 mg orally every six hours or 800 mg every 8 hours, to be taken with onset of menses for duration of typical symptoms). If this does not result in adequate pain relief, we switch to a fenamate, such as mefenamic acid (500 mg loading dose, 250 mg every six hours for three days). (See 'Nonsteroidal anti-inflammatory drugs' above.)

•Estrogen-progestin contraceptives – For individuals with dysmenorrhea who either desire contraception or for whom use of a contraceptive is acceptable, we suggest treatment with an estrogen-progestin hormonal contraceptive for first-line therapy (Grade 2C). There are no data that one dose or formulation is more effective than another. The choice depends upon patient preferences for dosing, cycle control, cost, availability, and side effects, among other variables. (See 'Hormonal contraception' above.)

•Progestin-only contraceptives – Progestin-only contraceptives have been less well studied for the treatment of dysmenorrhea compared with estrogen-progestin contraceptives, except for the 20 mcg levonorgestrel IUD. This IUD is associated with reductions in dysmenorrhea. (See 'Progestin-only methods' above.)

●Second tier medical management – For those with dysmenorrhea who do not respond to three to six cycles of NSAIDs and hormonal contraception, second-tier therapies include transcutaneous electrical nerve stimulation and gonadotropin-releasing hormone agonists/antagonists. The time required for treatment, side effects, and cost limit the use of these options. Patients who decline these treatments or do not improve then generally proceed with laparoscopy. (See 'Second-tier' above.)

●Additional options

•Role of laparoscopy – Patients whose symptoms persist are likely to have a gynecologic disease, such as endometriosis, causing their pain. We offer diagnostic laparoscopy to these patients and base subsequent treatment decisions on findings at laparoscopy. (See 'Role of laparoscopy' above.)

•Endometrial ablation – For patients whose dysmenorrhea persists in the setting of heavy menstrual bleeding, endometrial ablation may be an option. Hysterectomy is the definitive surgical therapy in patients who have completed childbearing. (See 'Surgery for refractory dysmenorrhea' above.)

•Supportive therapies – Although the evidence for supportive therapies such as behavioral counseling, complementary medicine, and dietary changes is weak, these interventions are unlikely to be harmful when used in moderation (for supplements in particular). Interested patients can add these approaches to their other treatment regimens at any time. (See 'Supportive therapies' above.)