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Dexfenfluramine - Miracle drug or Pandora's box?

The information below was initially written in early 1996 -- before dexfenfluramine was approved for use in the United States and obviously well before it was withdrawn from the market because of its association with Valvular Heart Disease. This information is provided to give a historical perspective on its use.

Obesity is a chronic illness requiring long-term treatment to achieve long-term results. In recent years, dexfenfluramine has become the standard for treatment and has resulted in the concept that prescribed medication should be thought of as a part of ongoing treatment. This is the rationale developed in the studies by Weintraub (Clin Pharmacol Ther 1992 May;51(5):619-33) combining phentermine with fenfluramine (two different appetite suppressants) to assist in the treatment of obesity.

Some clinicians are now proposing to prescribe dexfenfluramine on a long-term basis to help control obesity. Dexfenfluramine can assist with losing weight. In the United States, it is currently approved for up to one year usage. In the International Dexfenfluramine (INDEX) Study, the largest controlled study utilizing dexfenfluramine, patients were placed on either placebo (sugar pills) or dexfenfluramine for one year. Additionally, all patients were provided behavior modification and dietary instruction. Patients placed on placebo lost an average of 7.15 kilograms (~16 lbs.) compared to the dexfenfluramine group, which lost an average of 9.82 kilograms (~21 lbs.). In other words, the dexfenfluramine group lost on average an additional 5 3/4 lbs. after being on the medication for one year. Some patients, however, did have dramatic responses to dexfenfluramine.

There are, however, major clouds hanging over this drug. Dexfenfluramine appears to cause a serious medical condition called Primary Pulmonary Hypertension that affects an estimated1 in 17,000 patients treated for longer than 3 months (Abenhaim L, et. al. Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension. New England Journal of Medicine 335:609-616 August 29, 1996). The symptoms of this complication may be vague chest discomfort or development of an insidious feeling of shortness of breath. If one develops pulmonary hypertension, stopping the medication may or may not stop the disease process; a lung or a heart-lung transplant may be required.

Another potentially serious concern is that dexfenfluramine in high doses has been shown to cause significant damage to brain serotonin neurons. Dexfenfluramine appears to initially stimulate neurons to release serotonin, resulting in higher serotonin levels. However, with high doses (in rodents), these neurons appear to be damaged, resulting in depletion of serotonin. Low levels of serotonin are associated with sleep and mood disorders, especially depression.

In a well-controlled study performed by Una McCann, et al in The Journal of Pharmacology and Experimental Therapeutics (vol 269, no. 1, 1994: 792-798), squirrel monkeys (primates) given dexfenfluramine for only four days showed significant reductions of serotonin activity when their brains were examined 17 months later! The doses used were the human equivalent of about 1 mg. per kilogram, which is only two to three times higher than the manufacturer recommends for use in the United States on humans. This study seems to imply possible permanent brain changes (serotonergic neural injury) resulting from the short-term use of dexfenfluramine at higher than recommended dosages. At this time, it is unknown whether similar changes can occur in humans treated with long-term, high-dose dexfenfluramine, despite the fact that large numbers of people in Europe have used this medication.

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Content last modified: May 28, 2004

Copyright © 1996-2004 Michael D. Myers M.D. Inc.
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