By Leslie Shimp, Pharm.D., M.S.
Associate Professor of Pharmacy,
College of Pharmacy, University of Michigan
Consultant pharmacist, Department of Family Practice, Medical School,
University of Michigan
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By Leslie Shimp, Pharm.D., M.S. |
Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally effective in 66-90% of women with primary dysmenorrhea. Several factors such as the dose, regimen, and side effects can influence patient response. Education concerning appropriate product selection, dosing, and side effect management is especially important for women on nonprescription NSAID therapy. This article provides information on the optimal use of over-the-counter (OTC) products for dysmenorrhea, as well as guidelines for identifying primary dysmenorrhea and the women for whom OTC therapy can be recommended.
Dysmenorrhea, defined as difficult or painful menstruation, can be classified as primary or secondary disease.1 Primary dysmenorrhea is characterized by pain and related symptoms that occur at the time of menstruation in the absence of identifiable organic pelvic pathology (e.g., endometriosis). The pain associated with primary dysmenorrhea is a cramping type pain in the lower midabdominal or suprapubic area. The pain may radiate to the lower back or upper thighs. Related symptoms include nausea, vomiting, diarrhea, headache, fatigue, nervousness and dizziness.2 Symptoms usually begin at or shortly after the start of menses and last for about 48-72 hours.
Primary dysmenorrhea occurs most often in young women. It usually appears during adolescence or the early to mid-twenties and is less common past the age of 35 years. Primary dysmenorrhea occurs only during ovulatory cycles, and its prevalence increases from the early teen years to the late teens as the regularity of ovulation increases.1,3 Prevalence declines in women older than 30 years, peimarily due to the influence of pregnancy. During late pregnancy there is a decrease in uterine adrenergic nerves, and many do not regenerate after childbirth. 4
Several characteristics distinguish primary dysmenorrheal from secondary disease. Secondary dysmenorrheal results from identifiable pelvic pathology, such as pelvic inflammatory disease, endometriosis, ovarian cysts, benign uterine tumors, endometrial cancer, and congenital abnormalities. Women are usually 30 years of age or older when this condition first appears, and symptoms are typically not confined to the two or three days at the beginning of menses (see Table1).5
| Table 1: Distinguishing Primary and Secondary Dysmenorrhea | ||
|---|---|---|
| Primary | Secondary | |
| Age at Onset | mid to late teens, early 20s | usually 30 years or older |
| Duration of Pain | begins at onset of menses and lasts 48-72 hours | not always linked to menses; may continue throughout menses or occur at other times in the cycle |
| Gynecologic Health | no pelvic pathology | history of irregular menstrual cycles, menorrhagia, pelvic inflammatory disease, infertility |
Primary dysmenorrhea is thought to be related to prostaglandin synthesis by the uterus. Prostaglandin levels in women with primary dysmenorrhea may be 5-13 times greater than those in women without dysmenorrhea. In addition, the symptoms of primary dysmenorrheal are similar to the symptoms produced by exogenous administration of prostaglandins.1,3,6 In the uterus, prostaglandins cause contractions and vasoconstriction, sometimes resulting in uterine hypoxia (low oxygen) and pain.3 Women with dysmenorrhea have greater contraction pressures during contractions, a longer duration of individual contractions, and a shorter time between contractions. Both intrauterine pressure and the number of contractions are related to dysmenorrhea pain.1-3
NSAIDs and oral contraceptives are the principal drugs prescribed for the treatment of primary dysmenorrhea. In women who do not want to take oral contraceptives for birth control, NSAIDs are the drugs of choice. Currently, three NSAIDs are available as nonprescription products for the treatment of dysmenorrhea: ibuprofen 200 mg, ketoprofen 12.5 mg, and naproxen sodium 220 mg. These drugs should only be recommended to women with primary dysmenorrhea. A pharmacist can help a woman decide if self-treatment is appropriate by asking for her age and a description of symptoms, and ascertaining whether she has any medical conditions that may predispose her to secondary dysmenorrhea. In particular, symptoms should be consistent with the riming and characteristics of primary dysmenorrhea, and should not be severe or different from pain during previous menstrual cycles (see Table 2). Women with symptoms inconsistent with primary dysmenorrhea should be referred for medical evaluation of their symptoms. If symptoms are mild, aspirin or acetaminophen and/or local heat application may provide relief. However, NSAIDs are more effective for the treatment of primary dysmenorrhea.
| Table 2: Nonprescription Drugs for the Treatment of Dysmenorrhea | ||
|---|---|---|
| NSAIDS | Availability | Recommended regimen |
| Ibuprofen (Motrin IB™, Advil™, Midol™, others | 200 mg tablet | 1 tablet every 4-6 hours; may increase to 2 tablets if relief is not adequate (maximum dose per 24 hours: 1200 mg). |
| Naproxen Sodium (Aleve™) | 220 mg tablet | 1 tablet every 8-12 hours; an initial dose of 440 mg may improve effectiveness (maximum dose per 24 hours: 660 mg) |
| Ketoprofen (Artron™, Orudis KT™) | 12.5 mg tablet | 1 tablet every 4-6 hours; an initial dose of 25 mg may improve effectiveness (maximum dose per 24 hours: 75 mg) |
NSAIDs have several actions that can minimize dysmenorrhea symptoms. First, they inhibit the production of prostaglandins, which decreases uterine pressure and contractions. This improves blood flow to uterine tissue and reduces pain. In addition, by decreasing prostaglandins they decrease the associated symptoms which result from excess prostaglandins (e.g., nausea, vomiting, and headache).7 NSAIDs also have a direct analgesic effect.
All three nonprescription NSAIDs mentioned above are rapidly absorbed and reach peak plasma concentrations in about one to two hours. Rapid absorption and onset of action are both beneficial characteristics in treating primary dysmenorrhea.
Clinical trials have shown that NSAIDs provide good symptom relief in most women with primary dysmenorrhea (66-90%).3,8 Unfortunately, many women do not realize how effective NSAIDs are in managing primary dysmenorrhea. In one trial of adolescent girls, nearly 73% reported pain or discomfort with menstruation, but most of the girls had never taken a medication to relieve their symptoms.9
There are few comparative studies of the NSAIDs (both prescription and nonprescription products) used to treat primary dysmenorrhea. Generally, all the agents are effective when compared to a placebo, and no one particular NSAID appears to be more effective than another.5
Most of the clinical trials involving NSAIDs and dysmenorrhea utilized individual doses and total 24-hour doses that were higher than the labeled nonprescription doses (see Table 2). It is likely that not all women will be adequately treated with the doses recommended on the OTC product labels. The dosing instructions for all the nonprescription NSAIDs mention that some patients may require more than a single tablet. The manufacturers of ibuprofen suggest that 2 tablets (or 400 mg) be taken if adequate relief is not obtained from one tablet (not to exceed 1200 mg in a 24-hour period). Both ketoprofen and naproxen manufacturers suggest doubling the initial dose to provide better symptom relief. An initial dose of naproxen sodium 440 mg can be followed by a 220 mg dose 12 hours later for a 24-hour total dose of 660 mg. Similarly, an initial dose of 2 5 mg of ketoprofen can be used with a maximum of 25 mg every 4-6 hours, or 75 mg in a 24-hour period.
For the treatment of dysmenorrhea, NSAIDs provide optimal pain relief when taken on a scheduled basis, rather than as-needed.3, 10 The patient should be instructed to take these drugs according to a scheduled regimen for the first several days of her menses when prostaglandin levels are highest. Scheduled dosing helps to prevent cramping, as well as to relieve pain. It is recommended that women vary the dose (according to package insert directions) as well as the type of NSAID for 3-6 cycles, if necessary, to determine which dose or agent will adequately relieve their symptoms.1
Side effects from short-term NSAID therapy are mild. The most common side effect of all NSAIDs is gastrointestinal distress (e.g., upset stomach, nausea, abdominal cramps), which occurs in 3-9% of patients. Other side effects include constipation, diarrhea, gas, headache, dizziness, nervousness, ringing in the ears, and fluid retention. If a woman experiences side effects with a par-ocular NSAID, switching to another NSAID may solve the problem.
NSAIDs have several important drug-drug interactions. They can decrease the effectiveness of antihypertensive agents, including ACE inhibitors, beta blockers, alpha blockers, and diuretics. NSAIDs can also increase the potential for toxicity from anticoagulants, lithium, and high dose methotrexate.11
Women with dysmenorrhea who do not respond to nonprescription therapy should be referred to a clinician. Other treatment options include an increased dose of die nonprescription NSAID, a trial with one of the prescription NSAIDs, or the use of an oral contraceptive. About 80-90% of women with primary dysmenorrhea will experience adequate symptom control with the use of an NSAID, an oral contraceptive, or the combination.4 Treatment options for more difficult cases include therapy with a calcium channel blocker, tran-scutaneous electrical nerve stimulation (TENS), and uterine surgery.
Correct administration of nonprescription products and general knowledge about the condition can lead to effective self-management of dysmenorrhea. However, there are women who are not appropriate candidates for nonprescription therapy and others who will not be adequately treated with OTC drugs. Appropriate referral to other health care providers is an important aspect of managing dysmenorrhea. Pharmacists who take an active role in educating women about the treatment of dysmenorrhea will make a substantial contribution to the health of their patients.