Premenstrual Syndrome

Description

Alternative Names

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 seven days from menstruation and continued for four days into the cycle.

Acetaminophen

Acetaminophen (Tylenol, Anacin-3, Panodal, Phenaphen, and Valadol) is a good alternative to NSAIDs when stomach distress, ulcers, or allergic reactions prohibit their use. Products that combine acetaminophen agents that reduce other PMS symptoms are helpful. They include Pamprin, Midol, and Premsyn. Such agents 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 and citalopram (Celexa) are also being investigated for PMDD treatment.

Individuals taking SSRIs report not only relief from premenstrual dysphoric disorder but also 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 used or investigated 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 agent 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 study published in 2004 suggested that both dosing regimens are equally effective. Sertraline also may 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 on either a continuous or intermittent basis.

Other SSRIs are also being investigated for treatment of PMDD symptoms. For example, a 2002 study reported that Celexa was effective in a small group of women who had not responded to other SSRIs. Common side effects observed in people taking SSRIs are insomnia, gastrointestinal problems, anxiety, drowsiness, sweating, headache, and mild tremor. Sexual dysfunction, including delayed or loss of orgasm and low sexual drive, occurs in 30% to 40% of patients on SSRIs. Intermittent SSRI therapy, which involves taking the antidepressant only during the premenstrual period, may reduce frequency and severity of these side effects. SSRIs should not be taken concurrently with other antidepressant medication such as monoamine oxidase inhibitors (MAOIs).

Designer Antidepressants. Antidepressants with other actions are being studied.

• Venlafaxine (Effexor) is a so-called designer antidepressant known as 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. Two small studies reported benefits with the agent. Although a 2001 study reported no benefits with this agent, two other small studies, including one in 2002, reported relief. It should be noted that Serzone has been associated with increased risk of liver failure.

Studies are needed to determine if these agents 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 effects 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. It is important that this drug not be taken with either SSRIs or other antidepressants known as monoamine oxidase inhibitors (MAOIs).

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 agents for PMS related anxiety. Dependence is a common danger and can occur after as short a time as three 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 exacerbated. It should be noted that the drug also stimulates 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 agent known as an azapirone. A 2001 study reported that it reduced premenstrual irritability. Unlike the 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.

Hormone Therapies

Although hormone therapies are often prescribed for PMS, evidence suggests that they have little effect on these symptoms except in some cases. For example, some reports indicate that they may be helpful in women with asthma for reducing wheezing during the premenstrual period.

Hormonal Contraceptives. Until recently, most oral contraceptives (OCs, also called The Pill) that contain both progestins (either natural or synthetic forms of progesterone) and estrogen have not provided many benefits for women with PMS symptoms. Some women have reported worse symptoms after taking them. And, in fact, a 2002 study reported that women with a history of PMS or psychiatric symptoms were at higher risk for negative mood changes while on the Pill.

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

Still, the effects of OCs on premenstrual symptoms have not been rigorously studied, and formulations containing newer progestins may offer some benefits. Of interest is an OC (Yasmin) that contains estrogen and the progestin called drospirenone. Studies are suggesting that it may have specific and favorable effects on PMS symptoms, including significant improvement in psychological well-being, water retention, and appetite, compared to other OCs.

Side effects of OCs include nausea, breakthrough bleeding, breast tenderness, headache, and weight gain. Certain women should avoid oral contraceptives or use them with caution.

Note on Progestin-Only Contraceptives. Progestin-only contraceptives can include IUDs, implants, injections, as well as tablets. A major 2002 analysis supported previous studies in finding no benefits from most progestin-only contraceptives for women with PMS. Progestins, in fact, tend to increase negative moods. (Natural progesterones have the same negative effects as the synthetic progestins.) In spite of such evidence and other supporting studies, a 2002 British study reported that they were the most commonly prescribed agents for premenstrual symptoms.

GnRH Analogs. Potent hormonal agents called gonadotropin-releasing hormone (GnRH) agonists 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 agents, 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.

They include nafarelin (Synarel), goserelin (Zoladex), leuprolide (Lupron Depot), and histrelin (Supprelin). Some experts believe that GnRH analogs may be useful as first line therapy in some women with menstrual pain and irregular periods. These drugs are also effective for relieving symptoms of severe PMS, endometriosis, fibroids, and menorrhagia.

Commonly reported side effects (which can be severe in some women) include menopausal-like symptoms that include hot flashes, night sweat, and changes in the vagina, weight change, and depression. The side effects vary in intensity depending on the 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. Women ordinarily should not take them for more than six 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 six-month courses of GnRH agonists followed by an average of nine 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 agent called a bisphosphonate (alendronate or etidronate) may also be helpful.
• Other agents 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.

Adverse 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. Pregnant women or those trying to become pregnant should not take this drug, because it may cause birth defects.

Diuretics for Fluid Retention

Diuretics are prescription drugs that increase urination and help eliminate water and sodium 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, possibly leading 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 chose spironolactone.) Diuretics interact with a number of drugs, including certain antidepressants. Women who are candidates for diuretics should let their physicians know of any drugs or supplements that they are taking.