Emerging Drug Trends: Off-Label Uses and Misuses

Internal Medicine World ReportOctober 2007
Volume 0
Issue 0


is launching a web-exclusive column to discuss significant new evidence related to ongoing off-label uses of certain drugs with important clinical implications, highlighting emerging new uses and potential misuses of FDA-approved drugs. This column aims to help physicians as you face the decision of whether to prescribe a drug off-label, providing the most recent evidence of appropriate and inappropriate off-label uses.

Modafinil Shows Promise for Bipolar Depression

A study involving 85 patients with bipolar disorder suggests that modafinil (Provigil), a drug indicated for sleep disorders, effectively controls the depressive symptoms associated with bipolar disorder.

"There are very few treatments for the depressive phase of bipolar disorder, and as a result there is an urgent need to evaluate potential new therapeutics," said Mark Frye, MD, director of the Mayo Clinic Mood Disorders Clinic and Research Program, Rochester, Minn.

After 6 weeks, 44% of the patients in the modafinil group reported symptom improvement, and 39% said that their symptoms were in remission, compared with 23% and 18%, respectively, for the placebo group.

Modafinil is often called the "wake-up pill," because it is indicated to treat patients who suffer from excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder.


  • Belmaker RH. Modafinil add-on in the treatment of bipolar depression. Am J Psychiatry. 2007;164:1143-1145.

Statins Don't Prevent Prostate Cancer

New data from a large, community-based study refute previous findings that statins may reduce the risk of prostate cancer by limiting the output of male hormones that fuel prostate cancer.

"The public health significance is that our study provides evidence that statins may not have a clinically meaningful impact on testosterone in the blood, although further studies should be done," said coinvestigator Susan A. Hall, PhD, a research scientist at the New England Research Institutes in Watertown, Mass. "That doesn't mean that statins may be lowering prostate cancer risk through one or more alternative pathways, but it doesn't appear to be working through reduction of male hormones."

This study looked at a male subset of the Boston Area Community Health Survey, a population-based, National Institutes of Health-sponsored epidemiologic study. Of the 1812 men in the study, 237 were statin users. Blood data was analyzed for "free" or unbound testosterone, total testosterone, and other associated compounds.

Although men using statins had lower blood levels of androgens, such as testosterone, this was probably due to their poor health, not due to the statins. No relationship was found between statin use and levels of free testosterone and most associated compounds. A significant association was noted between statin use and level of total testosterone in the blood, but the association disappeared when patient age, body weight, and history of cardiovascular disease and diabetes were taken into account.


  • Hall SA, Page ST, Travison TG, et al. Do statins affect androgen levels in men? Results from the Boston area community health survey. Cancer Epidemiol Biomarkers Prev. 2007;16:1587-1594.

Off-Label Verapamil Use for Cluster Headaches Can Cause Heart Problems

The calcium-channel blocker verapamil (eg, Calan, Verelan), indicated for arrhythmias and high blood pressure, is often prescribed off-label to prevent cluster headaches. Such a use can lead to heart problems, investigators report.

"The benefit of taking verapamil to alleviate the devastating pain of cluster headaches has to be balanced against the risk of causing a heart abnormality that could progress into a more serious problem," said coinvestigator Peter Goadsby, MD, PhD, DSc, of the National Hospital for Neurology and Neurosurgery in Queen Square, London, and the University of California, San Francisco.

Some 108 patients with cluster headache received verapamil, in addition to undergoing electrocardiography (ECG) every 2 weeks. Verapamil dosing was titrated up until the headaches were stopped or side effects appeared.

Of this group, 21 patients (19%) had ECG-verified irregular heartbeats while taking verapamil. Although most cases were not serious, 1 patient required the implantation of a permanent pacemaker. And 37% of the patients showed slower-than-normal heart rate while taking verapamil; the problem was severe enough to cause 4 patients to discontinue treatment.

The investigators concluded that patients taking verapamil for cluster headaches should be closely monitored with frequent ECGs for the potential development of irregular heartbeats.


  • Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007;69:668-675.

Testosterone Patch Improves Hypoactive Sexual Desire in Women

Women with hypoactive sexual desire disorder benefit significantly from treatment with transdermally delivered testosterone?currently indicated for postmenopausal hot flashes and related symptoms?pooled data from 2 studies suggest.

"These findings not only confirm the clinical effectiveness of transdermal testosterone, but provide benchmarks for the degree of improvement in sexual function that all future therapies for this disorder should try to attain," said coinvestigator Jan Shifren, MD, associate professor of obstetrics, gynecology and reproductive biology, Harvard Medical School.The 2 randomized, double-blind, placebo-controlled trials included 132 surgically induced postmenopausal women with hypoactive sexual desire.

The women were interviewed after 6-months of treatment with transdermal testosterone therapy (300 µg/d). Among women reporting that the testosterone patch was "beneficial," a significant increase was seen in the frequency of satisfying sexual activity and sexual desire. These women reported an average increase in sexual activity of 4.4 times per 4 weeks; in contrast, women who did not report a benefit had only a 0.5 increase in activity per 4 weeks.

Compared with placebo, 2.4 times as many women receiving testosterone reported a "meaningful benefit" (52% vs 31%).


  • Kingsberg S, Shifren J, Wekselman K, et al. Evaluation of the clinical relevance of benefits associated with transdermal testosterone treatment in postmenopausal women with hypoactive sexual desire disorder. J Sex Med. 2007;4:1001-1008.

Beta-Blockers First Choice for Varicose Bleeding Prophylaxis

Beta-blockers, such as propranolol (Inderal)—indicated for the treatment of hypertension and the prevention of angina and myocardial infarction—should also be used as first-line therapy for preventing varicose bleeding in patients with cirrhosis and portal hypertension, investigators say.

"Beta-blockers should remain the first choice of prophylactic therapy in candidates for liver transplantation," the investigators report while emphasizing that banding should be used when beta-blockers are contraindicated.

"Both propranolol and endoscopic banding are similarly effective in reducing the incidence of variceal bleeding in cirrhotic patients with high-risk varices, but ligation can be complicated by severe and fatal bleeding and is significantly more expensive," they say. (The mean cost of treatment with propranolol was $1425 compared with $4289 for banding.)

Some 62 patients with Child B-C cirrhosis and high-risk esophageal varices were enrolled in the study. Participants were randomized to treatment with propranolol or to variceal banding.

Of the 31 patients receiving propranolol, 5 ended treatment early due to complications that included bradycardia, persistent hypotension, and vertigo. Of the 26 patients who continued treatment, 3 eventually bled from esophageal varices, and 2 died of bleeding. During the mean follow-up of 7.6 months, 10 of the patients underwent liver transplantation.

Of the 31 patients treated with ligation, 2 had dramatic hemorrhage within several days after the first treatment and required emergency interventions: 1 patient recovered and 1 died. The remaining patients underwent 3 ligations to eradicate varices. During the mean follow-up of almost 15 months, 2 patients died of liver failure, and 14 received a liver transplant.

Propranolol and endoscopic banding lowered the expected incidence of bleeding by about 30% after 1 year. Only banding was directly associated with a death.


  • Norberto L, Polege L, Cillo U, et al. A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation. Liver Transpl. 2007;13:1272-1278.
  • Boyer TD. Clinical trials for variceal bleeding: and the winner is?the patient. Liver Transpl. 2007;13:1212-1213.
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