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Objective: To investigate if phentermine treatment induces phentermine abuse, psychological dependence (addiction) or phentermine drug craving in overweight, obese and weight loss maintenance patients. To investigate whether amphetamine-like withdrawal occurs after abrupt cessation of long-term phentermine treatment., Design: Clinical intervention trial with interruption of phentermine treatment in long-term patients., Subjects: 269 obese, overweight or formerly obese subjects (age: 20-88 years, BMI: 21-74 kg m(-2)) treated with phentermine long-term (LTP, N=117), 1.1-21.1 years, or short-term (ATP, N=152), 4-22 days, with phentermine doses of 18.75-112.5 (LTP) and 15-93.75 (ATP) mg per day., Measurements: Module K of the Mini International Neuropsychiatric Interview modified for phentermine (MINI-SUD), Severity of Dependence Scale (SDS), 45-item Cocaine Craving Questionnaire-NOW (CCQ-NOW) modified for phentermine (PCQ-NOW), and Amphetamine Withdrawal Questionnaire (AWQ) modified for phentermine (PWQ)., Results: MINI-SUD interviews were negative for phentermine abuse or psychological dependence in all LTP patients. SDS examination scores were low for all LTP and ATP patients, indicating they were not psychologically dependent upon phentermine. PCQ-NOW scores were low for all LTP and ATP patients, indicating neither short-term nor long-term phentermine treatment had induced phentermine craving. Other than an increase in hunger or eating, amphetamine-like withdrawal symptoms did not occur upon abrupt phentermine cessation as measured by sequential PWQ scores., Conclusions: Phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity. Phentermine treatment does not induce phentermine drug craving, a hallmark sign of addiction. Amphetamine-like withdrawal does not occur upon abrupt treatment cessation even at doses much higher than commonly recommended and after treatment durations of up to 21 years.

Objective: A human pilot study testing the safety and effectiveness of NT (Number Ten), a dietary herbal supplement made from rhubarb, ginger, astragulus, red sage and turmeric, to reduce food intake and cause weight loss., Research Methods and Procedures: A total of 24 healthy women, 18-60 years, body mass index 25-35 kg/m(2) on no chronic medication were randomized to four groups of six: (1) oral freeze-dried NT 6 gm/day, (2) bed-dried NT 6 gm/day, (3) freeze-dried NT 12 gm/day or (4) placebo. Number Ten dose was escalated over 3 weeks and maintained for 8 weeks on a 700 kcal/day diet below maintenance. Food intake was measured at baseline and 4 weeks. Safety parameters were monitored weekly during dose escalation, week 6 and week 12., Results: Weight loss was 1.8 kg for placebo and 0.4 kg for 500 mg NT whereas the 250 mg bed- and freeze-dried NT gained 0.43 and 0.87 kg, respectively (P=NS). The food intake increased 74 kcal with 250 mg freeze-dried NT and decreased 193.7 kcal with 500 mg freeze-dried NT (P<0.01). There was a dose-related incidence of loose stools in the NT groups, but no other toxicity was seen. Number Ten was found to contain sennosides, known laxatives and gallic acid, which is known to give weight loss in rodents., Discussion: The human dose equivalent of NT used in this study was & frac16; and & frac112; of that shown to give well-tolerated weight loss in rodents. Number Ten will not be an effective dietary herbal supplement for the treatment of obesity owing to dose-limiting gastrointestinal toxicity.

Objective: Dropouts from clinical trials decrease quality and increase costs. Free participation, paid participation, and contingency contracting are three study retention methods. Contingency contracting, or depositing a fee to be refunded contingent upon attendance in a clinical trial, has been reported to decrease dropouts without affecting weight loss. These three methods of retention were compared with a commercial weight loss clinic's practice of charging nonrefundable fees., Methods and Procedures: Dropouts were compared in two studies testing mazindol, with one study using free care and the other using contingency contracting; two studies testing phenylpropanolamine, one using free care and the other using contingency contracting; and in studies with phenylpropanolamine on file with Thompson Medical Company using free care, paid participation, and contingency contracting., Results: The dropout rate was 50% at 8 weeks in a trial of mazindol with free care vs. 7% for contingency contracting (p<0.001). The two phenylpropanolamine studies gave the same weight losses, but the dropouts were 37% at 8 weeks for free care vs. 11% for contingency contracting (p<0.001). The studies of phenylpropanolamine on file at the Thompson Medical Company had 28% dropouts at 8 weeks using free care vs. 19% for paid participation (p<0.001), and 11% for contingency contracting (p<0.005). Dropouts with contingency contracting (11%) were not different from the commercial weight loss program (13%)., Discussion: Contingency contracting can decrease dropouts, improve quality, and decrease costs without affecting weight loss in clinical trials for obesity.

Objective: To evaluate, in compliant patients, the pharmaceutical costs of treating obesity with fenfluramine/mazindol, fenfluramine/phentermine, caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating obesity-related comorbid conditions and reducing cardiovascular risk., Methods and Procedures: Subjects were between 18 and 60 years of age with a BMI of >30 kg/m2. Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for diabetes, hyperlipidemia, or hypertension before and after treatment using fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol reduction was calculated for fenfluramine with mazindol or phentermine, caffeine with ephedrine, or mazindol alone, and compared to approved lipid-lowering medications., Results: Losses of 6% to 10% of initial body weight reduced pharmacy costs $122.64/month for insulin treated diabetes, $42.92/month for sulfonylurea-treated diabetes, $61.07/month for hyperlipidemia treated with medication, and $0.20/month for hypertension treated with medication. Blood pressure and laboratory evidence of insulin resistance improved in all medication groups. Caffeine/ephedrine was most cost-effective of the three treatments in reducing weight, cardiac risk, and LDL cholesterol., Discussion: Obesity medications produced a substantial weight loss in compliant patients and resulted in a net pharmaceutical cost savings compared to treating obesity related comorbid conditions.

Obesity is a chronic disease and requires ongoing treatment. Type 2 diabetes is associated with obesity and improves with weight loss. Diets of 800 kcal/d induce twice the weight loss induced by weight loss medications. The strength of weight loss medication, which should be used with diet and a lifestyle change program, is the maintenance of weight loss. Sibutramine and orlistat are the only two medications approved for the long-term treatment of obesity. Orlistat gives a reduction of low-density lipoprotein (LDL) cholesterol in excess of that expected with weight loss, and the drop in blood pressure expected with weight loss is not seen with sibutramine. Except in newly diagnosed patients with diabetes subjects, patients with diabetes lose half the weight of subjects who do not have diabetes when treated with weight loss medications. Metformin and, to a lesser extent, acarbose cause weight loss, making them attractive choices for the treatment of obese type 2 diabetic subjects. Repaglinide appears to be weight-neutral, but other medications for patients with diabetes can be associated with weight gain. Many new medications are in development for the treatment of obesity. These new medications act through a variety of mechanisms and will surely play an increasingly important role in the treatment of obese patients with type 2 diabetes.

Objective: The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed at 5%-30%. We studied 86 patients who had echocardiograms before treatment with appetite suppressants to determine the incidence of new cases and to evaluate the clinical implication of the echocardiographic findings., Research Methods and Procedures: We studied 69 men [Mean+/-Standard Deviation (S) age 49+/-8] and 17 women (mean+/-S age 50+/-7) who had 233 echocardiograms before, during, and after a weight-loss program that used predominantly fenfluramine (or dexfenfluramine) with mazindol (or phentermine). Mean drug exposure was 17 months. Blinded echocardiographic readings were performed to identify and grade aortic regurgitation (AR) or mitral regurgitation (MR)., Results: Seven of 86 patients (8%) had pre-existing regurgitation with five (6%) meeting our case definition. Thirteen (16.5%) of initially normal patients developed valvular regurgitation and were new cases. Of the new cases, 12 were grade I/IV AR and one was both grade II/III MR and II/IV AR. All 13 patients were asymptomatic, and only two aortic insufficiency murmurs could be auscultated. There was significantly greater risk for developing valvulopathy for those who took medications longer than 6 months (p = 0.03), and no new cases were observed in patients exposed for less than 8 months. No increased risk associated with age, presence of hypertension, or exposure to fenfluramine-phentermine combination was demonstrated. Although there was a higher incidence of new regurgitation in women (31% vs. 13% for men), this was not statistically significant (p = 0.093)., Discussion: Some patients who had normal echocardiograms at baseline developed cardiac valvular regurgitation after exposure to fenfluramine or dexfenfluramine with mazindol or phentermine. The development of valvulopathy was significantly correlated with duration of exposure. The clinical implications of echocardiographically demonstrated regurgitation are uncertain, since there were only two audible murmurs and no other clinically relevant signs or symptoms among the patients.

Objective: Phenylpropanolamine (PPA) and benzocaine are non-prescription medications approved for treating obesity. The dose of PPA for weight loss is 75 mg/day. PPA has the same chemical similarity to pseudoephedrine that amphetamine has to methamphetamine. Because benzocaine causes weight loss by altering taste and PPA by central appetite suppression, they may induce additional weight loss when combined. These studies explore the safety and efficacy of low-dose PPA, pseudoephedrine, and PPA with benzocaine in causing weight loss., Research Methods and Procedures: Study 1 compared PPA 12.5 mg tid with 25 mg tid and placebo in a 6-week trial in 108 obese subjects. Study 2 compared pseudoephedrine 120 mg/day and a placebo in a 12-week trial with 72 obese subjects. Study 3 compared 4 groups of 20 obese subjects using PPA 75 mg/day, benzocaine gum 96 mg/day, PPA with benzocaine gum, and a placebo over 12 weeks., Results: Both doses of PPA gave twice the weight loss of placebo, but the difference did not reach statistical significance. Pseudoephedrine was no different than placebo in inducing weight loss. The PPA with benzocaine group had more adverse events than the benzocaine group (p = 0.03), the placebo group (p = 0.03), or the PPA group (p = 0.09) without additional weight loss., Discussion: We conclude that further studies with low-dose PPA for weight loss are indicated, that pseudoephedrine is not effective for weight loss, and that adding benzocaine to phenylpropanolamine increases adverse effects without increasing weight loss.

Objective: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity., Research Methods and Procedures: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes., Results: Weight loss was dose-related and statistically significant vs. placebo (p<0.05) across all time-points for a 5 mg/day to 30 mg/day dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia., Discussion: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.

The combined analysis of parallel double-blind studies of prescription anorectic drugs in 1973 showed 0.23 kg/wk more weight loss than placebo at the end of the studies. In 1985, the combined studies of phenylpropanolamine (PPA) and PPA with caffeine gave 0.27 kg/wk more weight loss than placebo, but since 1985, this difference has dropped to 0.14 kg/wk in the combined studies with PPA. The incidence of adverse reactions in the combined studies with PPA were 19% and 14% for placebo (P less than 0.02). These adverse reactions were mild, however, and ceased with drug discontinuation. The two nonprescription anorectic drugs, PPA and benzocaine, and their combination, were compared in a 40-patient study. Benzocaine gave less weight loss than PPA (P less than 0.05 ANOVA). Thus, PPA is safe and effective for weight loss, appears less effective than prescription anorectics in studies exceeding 4 wk, and weight loss was not enhanced by combination with benzocaine.

It should be obvious from the foregoing discussion that, at the present time, there is not an acceptably safe and effective pharmacological treatment for obesity. This patent inadequacy of present drug regimens has spawned the investigation into the diverse pharmacological approaches reviewed in this paper as well as investigation into the intestinal bypass operation (see Chapter 10). We feel that the eventual, safe and effective therapy for obesity will come from the pharmacological realm. Glucose-blocking drugs, growth hormone analogues, and hydroxycitrate are but three of the potentially safe and effective approaches to the problem for the future. It will be truly fascinating to watch the development in the treatment of obesity and, specifically, the pharmacological treatment for this problem over the next five to ten years.

Mazindol, diethylpropion, and a placebo were compared with behavioral therapy for effectiveness in producing weight reduction in an outpatient obesity clinic. Each method was also compared in cost and harmful side effects. The patients were recruited from the middle and lower socioeconomic groups. Of the 120 patients beginning treatment, only 33 completed the entire 14-week study. There was no statistically significant difference in the weight loss among the treatment groups. The program of behavioral therapy was administered by a dietitian who as experienced in the techniques of behavior modification; the drug treatment groups were seen by physicians. We conclude that behavioral therapy may be the treatment of choice in an outpatient obese population since it requires little physician time, is less expensive, and avoids the side effects of anorectic drugs.