Premenstrual Syndrome Medication

No single treatment is universally effective, and studies with all therapies have not produced consistent results. Current recommendations in the literature regarding oral contraceptive pills are conflicting.^{[23, 24, 25, 26, 27, 28, 29, 16, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 21, 14, 43, 2, 44]}

Class Summary

These drugs act as potent inhibitors of gonadotropin secretion by binding competitively on GnRH receptors. They cause suppression, or down-regulation, of gonadotropins and, consequently, suppress ovarian and testicular steroidogenesis. This results in a hypoestrogenic state. The effects are reversible with discontinuation of drug therapy. GnRH agonists are not recommended for use in adolescents because of unknown effects on adolescent bone density.^[23]

Leuprolide (Lupron), nafarelin (Synarel)

GnRH agonists. Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Class Summary

These synthetic steroids probably work by a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and the interaction of the drug with sex hormone receptors. Depresses the output of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Not recommended for use in adolescents.

Danazol (Danocrine)

Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.

Class Summary

These agents are useful for managing the general aches, pains, and dysmenorrhea associated with PMS. The US Food and Drug Administration (FDA) has issued a warning regarding the increased risk of serious cardiovascular thrombotic events, myocardial infarction, and cerebrovascular events associated with cyclooxygenase-2 (COX-2) selective NSAIDs (eg, celecoxib, valdecoxib, and rofecoxib). Valdecoxib (Bextra) and rofecoxib (Vioxx) are no longer marketed. Nonselective NSAIDs (eg, ibuprofen, naproxen) also carry this risk. For more information, see the FDA Drug Information Page on COX-2 Selective and Nonselective NSAIDs.

Tolmetin (Tolectin), sulindac (Clinoril), diclofenac (Cataflam)

Acetic and salicylic acids NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), ketoprofen (Orudis)

Propionic acid NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Mefenamic acid (Ponstel), meclofenamate (Meclomen)

Fenamate NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Class Summary

These drugs are alternatives to standard NSAIDS and work by inhibiting prostaglandin synthesis via inhibition of COX-2. The FDA has issued a warning regarding the increased risk of serious cardiovascular thrombotic events, myocardial infarction, and cerebrovascular events associated with COX-2 selective NSAIDs (eg, celecoxib, valdecoxib, and rofecoxib). Valdecoxib (Bextra) and rofecoxib (Vioxx) are no longer marketed. Nonselective NSAIDs (eg, ibuprofen, naproxen) also carry this risk. For more information, see the FDA Drug Information Page on COX-2 Selective and Nonselective NSAIDs.

Celecoxib (Celebrex)

Inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased.

Class Summary

These agents are used for edema, bloating, weight fluctuations, and mastalgia of PMS.

Spironolactone (Aldactone)

Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Hydrochlorothiazide (HydroDiuril)

May be beneficial in reducing edema. Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.

Class Summary

The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac)^{[14, 43]} and sertraline (Zoloft)^{[27, 39, 44]} are the first-line drugs for severe emotional symptoms.^[41] They work best when taken throughout the month. Clomipramine (Anafranil) given for the full cycle or half-cycle has been effective in treatment of emotional symptoms. Nefazodone, an antidepressant that blocks serotonergic and noradrenergic uptake, recently was shown to be effective in relieving symptoms.

SSRIs are greatly preferred over the other classes of antidepressants. Because the adverse effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when treating a child or adolescent with mood disorder.

Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric population.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the FDA issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed because suicidality occurred in both treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.

However, a study of more than 65,000 children and adults treated for depression between 1992 and 2002 by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants.^[31] This is the largest study to date to address this issue.

Currently, evidence does not associate obsessive compulsive disorder (OCD) and other anxiety disorders treated with SSRIs with an increased risk of suicide. For more information, see the FDA Web site on Antidepressant Use in Children, Adolescents, and Adults.

In July 2006 the FDA issued a Public Health Advisory highlighting the dangers of taking SSRIs and triptans (eg, sumatriptan) concurrently. As both of these drug classes increase levels of serotonin, simultaneous use of them may lead to serotonin syndrome. The FDA recommends that those who are taking both medications speak with their physician before stopping either medication.

Fluoxetine (Sarafem), sertraline (Zoloft)

SSRIs are used to treat premenstrual dysphoric disorder.

Clomipramine (Anafranil)

A tricyclic antidepressant. Affects serotonin uptake whereas its metabolite desmethylclomipramine affects norepinephrine uptake.

Nefazodone (Serzone)

Antidepressant unrelated to the other antidepressant classes. Antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.

Class Summary

Alprazolam (Xanax) and buspirone (BuSpar) have been effective in helping the anxiety-related symptoms of PMS.

Alprazolam (Xanax)

A benzodiazepine antianxiety agent. Binds receptors at several sites within the central nervous system, including the limbic system and reticular formation. Effects may be mediated through GABA receptor system.

Buspirone (BuSpar)

An antianxiety agent not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. A 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in CNS. Has anxiolytic effect but may take up to 2-3 wk for full efficacy.

Class Summary

Studies have shown that calcium and magnesium deficiency may play a role in PMS; therefore, supplementation is suggested.^{[35, 36, 37]}

Calcium carbonate (Caltrate, Os-Cal)

Calcium moderates nerve and muscle-performance by regulating action potential excitation threshold.

Magnesium (Almora, Magonate)

Selectively causes a depletion of brain dopamine, which may alter mood. The most common adverse effect is diarrhea. May use other PO supplements, including magnesium oxide or magnesium hydroxide.

Class Summary

Combination oral contraceptive agents have been pursued as treatment for PMS due to their ovulation suppression effects. However, studies have suggested that treatment with combination oral contraceptive agents does not significantly improve symptoms compared to treatment with placebo.^{[42, 22, 28, 2, 45]}

Combination oral contraceptives (estrogen and progesterone)

Reduces secretion of LH and FSH from pituitary by decreasing amount of gonadotropin-releasing hormones.

Dysmenorrhea can be prevented altogether in some patients by use of OCs, although these agents are not approved by the FDA for this indication. OCs may be an appropriate treatment choice in patients who do not wish to conceive. The combination OCs suppress the hypothalamic-pituitary-ovarian axis and thereby inhibit ovulation and prevent PG production in the late luteal phase. This generally significantly reduces the amount of menstrual flow and effectively alleviates primary dysmenorrhea in most patients.

Combination OCs and depot medroxyprogesterone acetate provide effective pain relief and are associated with a reduced menstrual flow. The use of NSAIDs in combination with an OC may be necessary, especially during the first few cycles after initiation of the OC. The dose of ethinyl estradiol generally should be less than 50 mcg. A monophasic OC containing 30 mcg of ethinyl estradiol is a reasonable choice. To date, studies comparing the efficacy of various OC formulations in the management of dysmenorrhea have not been performed.