Dexfenfluramine - Miracle Drug or Pandora's Box?

The information below was initially written in early 1996 - before dexfenfluramine was withdrawn from the market because of its association with Valvular Heart Disease.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, this has become the standard for treatment and has resulted in the concept that prescribed medication should be thought of as a part of the 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 a dramatic response 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 (estimated) 1 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 (a primate) given dexfenfluramine for only four (4) 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 is recommending for use in the United States. This study would seem 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.

On a more positive note, a recent article (Una McCann, Jie Yuan, George Ricaurte, European Journal of Pharm 283 (1995) R5-R7) concluded that the neurotoxic effects of fenfluramine (the mixture of dexfenfluramine with its optical, non-active isomer L-fenfluramine) can be prevented when administered with fluoxetine, a serotonin re-uptake inhibitor. In this study, mice given fenfluramine for 6 days at a dosage known to cause neurotoxicity did not show any evidence of depletion of regional brain serotonin activity when their brains were examined two weeks later. Admittedly, this was a short-term study and mice are not the ideal model for studying neurotoxicity (primates are closer to humans).

However, this preliminary data seems to indicate that there may be ways to deal with the possible neurotoxicity of dexfenfluramine that may occur with long-term use. Caution is also needed in that combining dexfenfluramine or fenfluramine with a serotonin re-uptake inhibitor like fluoxetine may result in a serious condition referred to serotonin syndrome, a potentially life-threatening condition characterized by fever, hallucinations, agitation, elevated blood pressure, muscle spasms, and coma.

EDITORIAL NOTE: We already know that dexfenfluramine can result in primary pulmonary hypertension in a small percentage of individuals, but if taken by millions of people for prolonged periods of time, we may see hundreds of people affected by this serious complication. Additionally, it would seem prudent that a study be undertaken in Europe to assess what behavioral and where possible, neuropathologic changes have occurred in people previously treated long-term with dexfenfluramine. It would be a shame to attempt to improve our weight and subsequently our health by causing significantly more depression and other mood disorders in an already at-risk population.

Content written: 1996.

Last modified: August 2001.

Copyright © 1996 -2001 Michael D. Myers M.D. Inc.
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