Medications

Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandins, substances that dilate blood vessels and cause inflammation. NSAIDs are usually the first drugs tried for almost any kind of minor pain. There are dozens of NSAIDs. Aspirin is the most common. Among the most effective NSAIDs for menstrual disorders are ibuprofen (Advil, Motrin, Midol PMS), naproxen (Aleve, Naprosyn, Naprelan, Anaprox), and mefenamic acid (Ponstel). Studies have also indicated that they are most helpful when started 7 days before menstruation and continued for 4 days into the cycle.

Acetaminophen

Acetaminophen (Tylenol) is a good alternative to NSAIDs, especially when stomach problems, ulcers, or allergic reactions prohibit their use. Products that combine acetaminophen with other drugs that reduce PMS symptoms are helpful. Brands include Pamprin and Premsyn. Such drugs typically also include a diuretic to reduce fluid and an antihistamine. Little evidence exists to indicate whether they are more or less effective than NSAIDs or other mild pain relievers.

Antidepressants

Selective Serotonin-Reuptake Inhibitors. Selective serotonin-reuptake inhibitors (SSRIs) are drugs that keep higher levels of serotonin available in the brain. They have become the most effective treatments for premenstrual dysphoric disorder (PMDD) and for severe PMS symptoms. Three SSRIs are currently approved by the FDA for the treatment of PMDD symptoms. They are fluoxetine (Prozac, Sarafem), sertraline (Zoloft), and paroxetine (Paxil). Other SSRIs such as fluvoxamine (Luvox) and citalopram (Celexa) are also being investigated for PMDD treatment.

SSRIs may help not only premenstrual dysphoric disorder but also premenstrual physical symptoms, irritability, and tension. SSRIs appear to work much faster for relieving PMS-related depression than when used in major depression. These drugs are typically prescribed with either continuous (daily) dosing throughout the month or an intermittent dosing regimen. With intermittent dosing, women take the antidepressant during the 14-day premenstrual period of their luteal phase. This approach is also associated with fewer adverse effects than the standard regimens for major depression.

The following SSRIs are currently approved for PMS and PMDD:

• Sarafem was the first branded SSRI to be approved for premenstrual syndrome, including both physical and emotional symptoms. Approved in 2000, Sarafem contains the same ingredient (fluoxetine) as Prozac, but the drug is usually prescribed as intermittent therapy with daily dosing for the 14 days prior to the onset of menstruation. Studies show very positive effects on premenstrual dysphoric disorder, particularly at 20 mg. According to a 2003 study, once a woman stops this treatment, PMS symptoms may recur in the following cycle.
• Sertraline (Zoloft) was approved in 2000 for treating PMDD as both a daily dose and intermittent therapy. A 2004 study suggested that both dosing regimens are effective. Sertraline may also have specific benefits, including improvement in sleep and memory and a lower risk for prolactin production. (Overproduction of this hormone has been associated with bone loss and absence of menstruation.)
• Paroxetine (Paxil) was approved by the FDA in 2003 for the treatment of PMDD symptoms. As with fluoxetine and sertraline, it can be taken either on a continuous or intermittent basis. In 2006, the FDA warned that paroxetine may increase suicidal behavior, particularly in young adults. Women planning on becoming pregnant should be aware that paroxetine may cause birth defects if it is taken during the first trimester of pregnancy.

General side effects of SSRIs may include nausea, drowsiness, headache, weight gain and sexual dysfunction.

Designer Antidepressants. Non-SSRI antidepressants sometimes prescribed for PMDD include:

• Venlafaxine (Effexor) is a serotonin-noradrenaline reuptake inhibitor. It is similar to fluoxetine (Prozac) in effectiveness and tolerability for most patients. Some trials have reported significant improvement in premenstrual dysphoria. Research is needed to determine whether intermittent treatment would be useful.
• Studies have been mixed on the use of intermittent treatment with nefazodone (Serzone), another designer antidepressant. Patients should be aware that nefazodone has been associated with increased risk of liver failure.

Studies are needed to determine if these drugs offer any additional benefits compared to standard SSRIs.

Tricyclics. Before the introduction of SSRIs, tricyclics, such as desipramine (Norpramin) or amitriptyline (Elavil, Endep), had been the standard treatment for depression. They are not very useful, in general, for premenstrual dysphoric disorder or other PMS symptoms. One exception may be clomipramine (Anafranil), which affects serotonin and has been helpful for some women. Patients report more side effects with Anafranil than with SSRIs, although low doses are used for premenstrual syndrome and may be beneficial for some women. Patients should not take tricyclics with either SSRIs or other antidepressants known as monoamine oxidase inhibitors (MAOIs).

[For more information on antidepressants, see In-Depth Report #08: Depression.]

Antianxiety Drugs

Antianxiety drugs (called anxiolytics) may be helpful for women with severe premenstrual anxiety that is not relieved by SSRIs or other treatments.

Benzodiazepines. The standard anxiolytics are the benzodiazepines, with alprazolam (Xanax) most often used for PMS. Experts, however, generally do not recommend these drugs for PMS-related anxiety. Dependence is a common danger and can occur after as short a time as 3 months of use. (Using Xanax for only a few days per month when symptoms are most severe reduces this risk.) Common side effects are daytime drowsiness and a hung-over feeling. Respiratory problems may be worsened. Benzodiazepines also stimulate an increase in appetite, particularly for fats, during the premenstrual cycle. Overdose is very serious, although rarely fatal. Benzodiazepines are potentially dangerous when used in combination with alcohol.

Buspirone. Buspirone (BuSpar) is a unique anti-anxiety drug known as an azapirone. A 2001 study reported that it reduced premenstrual irritability. Unlike benzodiazepines, buspirone is not addictive. Buspirone also seems to have less pronounced side effects than benzodiazepines and no withdrawal effects, even when the drug is discontinued quickly. Common side effects include dizziness, drowsiness, and nausea.

[For more information, see In-Depth Report #28: Anxiety.]

Hormone Therapies

Birth Control Pills. Most oral contraceptives (OCs) combine progestins (either natural or synthetic forms of progesterone) and estrogen (usually ethinyl estradiol). Some doctors advise women with PMS to skip the 7-day placebo interval of their birth control medication and instead use the active drugs on a continuous basis to avoid monthly menstruation.

New OCs are also being developed to specifically treat the mood symptoms associated with premenstrual dysmorphic disorder (PMDD):

• Yaz is a new low-dose birth control pill approved in 2006. It combines the estrogen estradiol with a new type of progestin called drospirenone. In clinical trials, Yaz helped improve mood and relieve PMDD symptoms when used in a 24/4 dosing regimen (24 days active pills, 4 days placebo pills). The FDA is considering approving Yaz for treatment of PMDD.
• Lybrel is a low-dose combined contraceptive that contains estradiol and levonorgestrel. The FDA is currently reviewing Lybrel. If approved, Lybrel will be the first birth control pill taken on a continuous basis with no pill-free interval. Lybrel is designed to completely eliminate periods and, therefore, may also help eliminate PMS. In clinical trials, women who took Lybrel experienced relief of PMS symptoms within a month of starting the drug.

Side effects of OCs include nausea, breakthrough bleeding, breast tenderness, headache, and weight gain. Women who smoke, or who are at risk for blood clots or stroke, should avoid oral contraceptives or use them with caution.

Click the icon to see an illustrated series detailing the birth control pill.

GnRH Agonists. Gonadotropin-releasing hormone (GnRH) agonists (also called analogs) are powerful hormonal drugs that suppress ovulation and, thereby, the hormonal fluctuations that produce PMS. They are sometimes used for very severe PMS symptoms and to improve breast tenderness, fatigue, and irritability. (These drugs, in fact, are sometimes used to rule out or confirm a diagnosis of PMS. If symptoms persist while the drug is being taken, then PMS is unlikely to be their cause.) GnRH analogs, however, appear to have little effect on depression.

GnRH agonists include nafarelin (Synarel), goserelin (Zoladex), leuprolide (Lupron Depot), and histrelin (Supprelin). Some experts believe that GnRH analogs may be useful as first-line therapy for women with severe menstrual pain and irregular periods.

Commonly reported side effects (which can be severe in some women) include menopausal-like symptoms that include hot flashes, night sweat, weight change, and depression. The side effects vary in intensity depending on the particular GnRH agonist. They may be more intense with leuprolide and persist after the drug has been stopped.

The most important concern is possible osteoporosis from estrogen loss. Doctors recommend that women not take these drugs for more than 6 months. Certain approaches may preserve enough estrogen to protect bones and still effectively relieve endometriosis symptoms:

Click the icon to see an image of osteoporosis.

• Add-back therapy, which provides doses of estrogen and progestin that are high enough to maintain bone density, but are too low to offset the beneficial effects of the GnRH agonist.
• Intermittent leuprolide, which uses repeated 6-month courses of GnRH agonists followed by an average of 9 months of symptom control only.
• Taking GnRH agonists in very low doses is an alternate approach, but is still largely untested.
• Adding a bone-protective drug called a bisphosphonate (such as alendronate or etidronate) may also be helpful.
• Other drugs are being tested in combination with a GnRH agonist to preserve bone. They include parathyroid hormone or tibolone (available in Europe). Tibolone is known as a selective estrogen-receptor modulator (SERM), which means it has some, but not all, effects of estrogen.

Danazol. Danazol (Danocrine) is a synthetic substance that resembles male hormones and should be used only if other therapies fail. It suppresses estrogen and menstruation and is used in low doses for severe PMS. It is particularly useful for premenstrual migraines. Taking it only during the luteal phase relieves cyclical mastalgia (severe breast pain) and avoids major side effects, but this intermittent regimen has no effect on other PMS symptoms.

Side effects from continuous use of Danazol can be severe. They include facial hair growth, deepening of the voice, weight gain, acne, and dandruff. Danazol also increases the risk for unhealthy cholesterol levels. A few cases of blood clots and strokes have been reported. Women who are trying to become pregnant should not take this drug, because it may cause birth defects.

Diuretics for Fluid Retention

Diuretics are drugs that increase urination and help eliminate water and salt from the body. They reduce bloating in women with PMS and also have a beneficial effect on mood, breast tenderness, and food craving. Diuretics can have considerable side effects and should not be used for mild or moderate PMS symptoms.

Spironolactone (Aldactone) is most commonly used for PMS. Other common diuretics include hydrochlorothiazide (Esidrix, HydroDiuril) and furosemide (Lasix). Unless potassium is replaced, many diuretics deplete the body's supply of potassium, which can lead to heart rhythm disturbances. Spironolactone, however, is known as a potassium-sparing drug and does not have this problem. (Of note, women should be sure not to take additional potassium if they are taking spironolactone.) Diuretics interact with a number of other drugs, including certain antidepressants. Women who are considering diuretics should let their doctors know of any other drugs or supplements that they are taking.