Phentermine Combined with Fenfluramine ("Phen/Fen Diet"): How Well Does this Combination Work?
IMPORTANT
NOTICE:
The information below was written before fenfluramine was withdrawn from the market because of its association with Valvular Heart Disease. This information is provided to give some perspective on the past use of this combination.
Most people have heard of combining phentermine with fenfluramine ("phen/fen diet") in an attempt to control weight. Michael Weintraub, et al in a series of studies (Long-term weight control Study I , II, III, IV, V, VI, & VII in Clin Pharmacol Ther; May 1992) studied these medications in individuals over a period of 210 weeks. Both medications are anorexics (appetite suppressants) that help diminish appetite by different mechanisms of action. Phentermine is a stimulant acting through noradrenergic and dopaminergic pathways resulting in decreased appetite and less frequent eating. Fenfluramine acts through serotonergic mechanisms resulting in a feeling of increased satiety. Phentermine may produce "mild" side effects such as nervousness, irritability, insomnia, agitation, dizziness, dry mouth, constipation, elevated blood pressure, and rapid or irregular heart beats.
Fenfluramine may produce somewhat opposite effects with drowsiness, sedation, diarrhea, and depression. Both medications can lead to serious side effects with fenfluramine being associated with Primary Pulmonary Hypertension, a life-threatening complication. Furthermore, in July 1997, a new complication (Valvular Heart Disease) was found to be associated with the use of "phen/fen" (for more information about possible side effects, please see FDA Recall). The thinking was that by combining these two medications, one could take advantage of their different pharmacologic actions getting, in essence, better effectiveness while (hopefully) minimizing the "mild" side effects. The results of the studies are summarized below.
Patient participation
Patients were 18 to 60 years of age weighing between 130% and 180% of their ideal body weights according to the 1983 Metropolitan Life Insurance Tables. The patients were in good health, not taking any long-term medications and did not have hypertension (high blood pressure), diabetes or other chronic diseases.Medication
Phentermine resin (15 mg) combined with Fenfluramine (60 mg)Behavior therapy
Active and ongoing behavior therapy with professionals trained in behavior modification techniques was an integral part of the study.Caloric restriction
All individuals received individualized dietary counseling by dieticians to help limit calorie consumption to between 1500 - 1800 kcal per day for men and between 1000 - 1200 kcal per day for women.Exercise
The participants in the study were started on graded exercise programs to expend at least an extra 300 kcal three times per week over their usual daily activities.Medical monitoring
All participants were seen by physicians at regular intervals during the study with periodic laboratory and electrocardiographic monitoring.
Results at 34 weeks
-
Placebo patients
(no medication but all other components as noted above):
4.6 kg (~10 lb.) average weight loss.
Medication patients: (medication and all other components as noted above): 14.2 kg (~30 lb.) average weight loss.
The study continued
Between weeks 34 and 104, all patients were placed on medication (including the placebo treated patients). During this two year time, 31% of the patients left the study and about 50% of these (or about 15% overall) left the study because of medication related side effects. During this time, behavioral and dietary therapy along with exercise and medical monitoring were on-going. Some patients were placed on intermittent medication (during October to January and April to June) while others (25% of the remaining group) who did not lose more than 10% of their initial weight were placed on an augmented dose (30 mg) of phentermine combined with fenfluramine (60 mg).Results at 104 weeks (83 of the 121 people who started the study):
Continuous Medication (39% of remaining participants): 12.6 kg.(~27 lb.) average weight lossIntermittent Medication (39% of remaining participants): 11.5 kg (~25 lb.) average weight loss
Augmented Medication group (22% of remaining participants): 6.5 kg (~ 14 lb.) average weight loss.
Average weight loss of the 83 participants making it to week 104: 10.8 kg (~23 lb.) weight loss
The study continued
Between weeks 104 and 156, attempts were made to optimize response to the medication by adjusting the dosages in an attempt to achieve a body weight of 120% or less of ideal body weight. At the end of 156 weeks, 59 patients out of 121 remained in the study. The dosages and results after 156 weeks are as shown:Group I (Phentermine 15 mg and fenfluramine 30 mg) [2 participants out of 59 remaining]:
In other words, all groups continued to gain weight (on average) although all remaining individuals were on medication. The average weight of the remaining group of 59 was 9.4 kg (~21 lbs) less than when they started the study 156 weeks before.Weight change from week 0: -14.1 kgFrom week 104: +7.6 kg
Group II (Phentermine 15 mg and fenfluramine 60 mg) [14 participants out of 59 remaining]:
Weight change from week 0: -10.9 kgFrom week 104: +2.7 kg
Group III (Phentermine 15 mg and fenfluramine 60 mg but medication used intermittently weeks 104-156) [7 participants out of 59 remaining]:
Weight change from week 0: -8.8 kgFrom week 104: +4.0 kg
Group IV (Phentermine 30 mg and fenfluramine 60 mg) [9 participants out of 59 remaining]:
Weight change from week 0: -7.7 kgFrom week 104: +3.8 kg
Group V (Phentermine 30 mg and fenfluramine 60 mg in the morning and additional fenfluramine 30 mg in the evening) [8 participants out of 59 remaining]:
Weight change from week 0: -10.5 kgFrom week 104: +3.0 kg
Group VI (Phentermine 30 mg and fenfluramine 60 mg in the morning and additional fenfluramine 60 mg in the evening) [19 participants out of 59 remaining]:
Weight change from week 0: -8.4 kgFrom week 104: +4.0 kg
The study continued
The remaining participants were again randomized to either receive daily doses of phentermine 15 mg combined with fenfluramine 60 mg or placebo. Behavior modification, dietary instruction, exercise, and physician visits continued for both groups. Both groups continued to gain weight but the medication group gained weight slower (4.4 kg gain between weeks 156 and 190) than the placebo group (6.9 kg gain between weeks 156 and 190). Overall, the remaining participants (51 of the initial 121 that started) weighed, on average, 4.1 kg (~9 lbs.) less than when they started the study 190 weeks before.And the study continued
Between 190 and 210 weeks, all participants were tapered-off their medication. The behavior modification, dietary instruction, physician monitoring, and exercise were continued. At the end of the study, the remaining 48 participants were, on average, 1.4 kg (~3 lbs) less than when they started the study. However, 7 of the remaining participants were 10% or more below their initial body weights.
Conclusions
1) Medication (phentermine + fenfluramine) in a program combining behavior modification, dietary instruction, exercise, and medical monitoring will assist with weight loss to a moderate degree with the greatest weight loss occurring within the first year with the weight gradually returning toward baseline despite continued intervention.2) The average weight loss with the medication protocol (program) peaked at 14 kg at week 34.
3) Patients who were treated only with dietary instruction, behavior modification, exercise intervention, and physician monitoring lost an average of 4.6 kg at week 34.
4) All patients received on-going dietary instruction, behavior modification, physician monitoring and exercise intervention. Although the total weight loss was small at week 210 (~3 lbs in the participants who continued), the natural history of obesity is to gain 1 to 2% of body weight per year and thus there was some measure of success from this program.
5) There is no evidence that the body weight control mechanism was reset to a lower level from long-term use of medication.
6) The effect of using medication without concomitant dietary, behavioral, exercise intervention, and physician monitoring are unknown.
7) Other modalities of treatment need to be employed to assist in attaining long term weight loss.
Content last modified:
1998
Copyright © 1996 -2001
Michael D. Myers M.D. Inc.
All rights reserved.
The above information is for general purposes only and should not be construed as definitive or binding medical advice. Because each person is medically different, individuals should consult their own personal physicians for specific information and/or treatment recommendations.