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Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double-blind placebo-controlled pilot study in adolescents

Abstract

OBJECTIVE: The present study was performed to investigate the efficacy and safety of a caffeine/ephedrine (CE) mixture in obese adolescents.

SUBJECTS: Thirty-two (m/f=16/16) obese children were included into the study. They were treated by diet (calculated daily energy requirement minus 500 kcal) and either CE or placebo (PL) for 20 weeks in a randomized double-blind placebo-controlled trial. Those weighing less than 80 kg took one tablet three times (100 mg/10 mg), whereas those weighing more than 80 kg took two tablets three times per day. There were three dropouts (girls) from the PL group. The age, weight body mass index (BMI) values (mean (range)) of the PL and CE groups were 16.0 (14.3–17.6) and 16.0 (14.2–17.7) y, 103.0 (77.2–126.4) and 104.8 (69.8–150.2) kg, 35.2 (28.3–42.3) and 36.5 (31.3–51.8) kg/m2, respectively.

RESULTS: The decrease in relative body weight, BMI and body fat (measured by bioelectric impedance) was significantly (P<0.05) greater in the CE group (mean±s.d.; 14.4±10.5%, 2.9±1.9 kg/m2, 6.6±6.0 kg) than in the PL group (2.2±5.8%, 0.5±1.6 kg/m2, 0.5±2.7 kg). Relative body weight decreased by more than 5% in 81% of the CE group, out only in 31% of the PL group. Adverse events were negligible and did not differ between the CE and PL groups. Withdrawal symptoms were mild, transient and their frequency and severity were not different between the placebo and active groups.

CONCLUSION: According to the present pilot study, CE can be a safe and effective compound for the treatment of obesity in adolescents.

Introduction

Obesity is a major health problem in affluent countries because of its high prevalence and its strong linkage to type 2 diabetes, hypertension, cardiovascular diseases, etc. These diseases generally do not become apparent during childhood but they have their origin in that age. Our recent investigations1 demonstrated that decreased glucose tolerance, hyperinsulinaemia, hypertension, dyslipidaemia and the combination of these abnormalities (multimetabolic syndrome) are already present in obese children. The prevalence of childhood obesity is high and still increasing in most countries.2 In spite of the very poor efficacy of the currently accepted weight-losing regimens, the administration of appetite suppressants or thermogenic drugs is being avoided in children and adolescents since no controlled investigations have been performed to prove the efficacy and safety of any of the available drugs. Numerous studies have proved in adults that a low-dose mixture of ephedrine and caffeine supports weight loss, preserves lean body mass and is without significant side effects and withdrawal symptoms or the development of drug dependency.3,4,5 The aim of the present study was to obtain data on the effects and side effects of an ephedrine/caffeine mixture in obese adolescents.

Subjects and methods

Study design and protocol

The subjects were assigned to receive either placebo or drug treatment for 20 weeks, in a randomized double-blind protocol. The active tablets contained 10 mg ephedrine and 100 mg caffeine. The treatment was gradually instituted starting with one tablet per day increasing the dose to one tablet three times daily in those weighing less than 80 kg and to two tablets three times daily in those weighing more than 80 kg. The maximal dose was reached by the end of the second or third week in the case of the low and high dose, respectively. After the 20th week of treatment the patients were weaned gradually (2×1 or 2 tablets daily for 3 days, then 1×1 or 2 tablets daily for another 3 days, then treatment was terminated).

The ephedrine/caffeine mixture tablets and the identical placebo tablets were prepared and packed by Nycomed DAK Pharmaceutical Company (Roskilde, Denmark).

The patients were evaluated before the start, at weeks 2, 8, 12, 16, 20, and at the follow-up visit (5 days to 2 weeks after the termination of treatment). Detailed physical assessment, anthropometry (weight, height, skinfolds at five sites, waist and hip circumference), body composition analysis, blood pressure and heart rate measurement, and monitoring of side effects using prestructured case report forms were performed at each visit. Withdrawal symptoms were checked and evaluated using a questionnaire during the follow-up visit.

At entry and throughout the study general advice was given about decreasing dietary energy intake (calculated daily energy requirement minus 500 kcal) and fat content (less than 30% of the total daily energy intake), and physical activity was encouraged. Consumption of coffee was prohibited.

The trial was run in accordance with the Declaration of Helsinki II and was approved by the local and the Hungarian National Ethical Committees and by the Hungarian National Pharmaceutical Institute.

Blood glucose, plasma insulin, thyrotrophin (TSH), free thyroxine (fT4), triiodothyronine (T3), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, apolipoprotein A1 and B, and for standard safety screening haemoglobin, haematocrit, white blood cell and platelet count, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), bilirubin, alkaline phosphatase (ALP), serum albumin and creatinine concentrations were measured from fasting blood samples. Urine was checked for glucose and protein at start and at week 8 and 20. Physical fitness testing was performed before the start and on week 20 to check cardiovascular side effects. Postabsorptive resting metabolic rate (RMR) and respiratory quotient (RQ) were measured at the start and on the 4th and 20th weeks.

Subjects

Thirty two obese adolescents (16 males, 16 females), in whom conventional dietary treatment was not successful, were enrolled into the study. The inclusion criteria were age between 14 and 18 y (Tanner stage: III–V); relative body weight >140%; and informed consent signed by the patient and the parents. The exclusion criteria were hypertension (systolic blood pressure (BP)>140 mmHg and/or diastolic BP≥ 100 mmHg); any metabolic or endocrine disease; psychiatric or somatic disease; any drug treatment; evidence of alcohol or drug abuse; treatment with methylxanthines less than 1 month prior to the start of the study; weight loss of more than 5 kg 3 months prior to the start of the study; and any contraindication to the trial medication.

Three of the 32 subjects enrolled initially defaulted because of difficulty in keeping follow-up appointments. These three patients were all girls and happened to belong to the placebo group. Of the 29 subjects who completed the study, 16 were in the active group and 13 in the placebo group. The most important clinical data of the per protocol patients are shown in Table 1.

Table 1 Anthropometric data of the per protocol patients at the beginning of the trial (mean±s.d.)

Methods

Anthropometric measurements were carried out by the same investigator throughout the study. Body weight was obtained in light clothing, without shoes, to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm by Holtain stadiometer without shoes. Body mass index (BMI) was calculated by dividing weight (kg) by squared height (m2). Relative body weight was calculated by dividing actual body weight by expected body weight for height6 and multiplied by 100. Skinfold thickness measurements (triceps, biceps, supra-iliac, sub-scapular and calf) were performed in triplicate on the left side of the body using Holtain calliper. Body composition was determined by the analysis of bioelectric impedance (BIA 101, RJL Systems, Detroit), using the equations of Wabitsch et al.7 Waist:hip ratio (WHR) was calculated as the ratio of the minimal waist circumference to the circumference of the maximal gluteal protuberance to assess body fat distribution.

RMR was measured after an overnight fast by means of a Deltatrac metabolic cart (Datex Instrumentarium Corp., Helsinki, Finland), using the ventilated hood technique. After achieving steady-state (which took typically 5–10 min) the RMR was measured for 30–45 min. Energy expenditure was derived from the measured oxygen uptake and carbon dioxide output according to the formula of Lusk.8

Physical fitness testing was carried out on treadmill (Jager EOS sprint) (with continuous measurement of expired oxygen and carbon dioxide, continuous blood pressure and ECG monitoring) according to a continuously incrementing (ramp pattern) exercise protocol, where the slope and the speed increase in 20 steps until the predicted maximal workload (Watt/kg) was achieved.9 Exercise duration (ED), physical working capacity at 170 beat/min (PWC-170) and maximal oxygen consumption (VO2max) were determined to characterize the fitness of the cardiorespiratory system.

Plasma glucose concentrations were measured by the glucose oxidase method and plasma immunoreactive insulin concentrations using radioimmunoassay kits from the Isotope Institute of the Hungarian Academy of Sciences (Budapest, Hungary).

Plasma total cholesterol, HDL cholesterol and triacylglycerol concentrations were determined enzymatically with Boehringer (Boehringer Mannheim, Mannheim, Germany) kits (precipitation method for HDL-cholesterol).

Plasma apolipoprotein A1 (apoA1) and B (apoB) concentrations were determined using liquid-phase immunoprecipitation assays with turbidimetric endpoint detection (Turbox, Orion Diagnostica, Espoo, Finland). Plasma TSH, T3 and free T4 concentrations were measured by ELISA method. Safety laboratory tests (ASAT, LDH, ALP, albumin, bilirubin, creatinine, haemoglobin, haematocrit, white blood cell and thrombocyte count) were performed with standard laboratory techniques.

The presence or absence of side effects (nausea, insomnia, tremor, dizziness, palpitation and other) was checked seven times (weeks 2, 4, 8, 12, 16, 20 and at follow-up) by pre-prepared questionnaire where side effects were graded according to severity (non, mild, moderate, severe). Withdrawal symptoms were recorded by the patients three times, on the first, third and fifth day of the weaning period. The patients were asked to grade the severity of sweating, palpitation, tremor, nervousness, nausea or vomiting, diarrhoea, insomnia and malaise.

Statistical analysis

All the results are expressed as mean±s.d. unless stated otherwise. Statistical differences were assessed using the unpaired and paired Student's t-test where baseline anthropometric parameters of the two groups were compared. Changes in physical fitness parameters between treatment groups and within groups at week 0 and week 20 were evaluated by unpaired and paired Student's t-test. Analysis of variance followed by the Fisher least significant difference comparison test were used to compare the changes of anthropometric parameters, laboratory values, blood pressure, heart rate and resting metabolic rate within and between treatment groups in time. Analysis of covariance was used to standardize RMR for body weight. Differences in frequency of side effects and withdrawal symptoms were assessed by Fisher's exact test.

There were no significant differences between genders in baseline values (laboratory and anthropometric) and in response to treatments, therefore data of females and males were combined.

Results

The baseline anthropometric (Table 1), laboratory (Table 2), blood pressure and heart rate (Table 3) and RMR (Table 4) values of the treatment groups were comparable. All patients except one girl (Tanner stage 4) had complete sexual development (Tanner stage 5).

Table 2 Laboratory results at weeks 0, 8 and 20 in the placebo (PL, n=13) and active (CE, n=16) groups (mean±s.d.)
Table 3 Blood pressure (mmHg) and heart rate (beat/min) values during the trial in the placebo (PL, n=13) and active (CE, n=16) groups (mean±s.d.)
Table 4 Resting metabolic rate (RMR) at weeks 0, 4 and 20 of the treatment period in the placebo and active groups (mean±s.d.)

The mean cumulative weight loss over the 20-week study was 7.9±6.0 kg in the active group vs 0.5±4.3 kg for the placebo group. Analysis of variance within groups revealed a significant change in weight over time in the active group (P<0.01), while no difference over time was observed in the placebo group. Multiple comparisons testing within active group revealed further significant differences between weights at weeks 2, 4, 8, 12, 16 and 20 compared to baseline. No such differences were found in the placebo group (Figure 1). Significant change in relative body weight (decrease in RBW ≥5%) was observed in 30.8% of the PL and 81.3% of the CE group.

Figure 1
figure1

Cumulative weight loss in the placebo (n=13) and in the active (n=16, treated with caffeine/ephedrine mixture) groups. +P<0.05, *P<0.01 placebo vs active; #P<0.05, ##P<0.01 vs week 0 (ANOVA).

The weight loss was mainly due to the decrease in body fat (Figure 2). The cumulative change in body fat was significant in the active group from week 4 onwards, while it was not significant in the placebo group. Lean body mass was fairly well preserved (Figure 3). The cumulative change in LBM at week 20 was not significantly different in the two groups (PL: 0.02±3.0 kg; CE:−1.3±3.2 kg).

Figure 2
figure2

Cumulative change in body fat in the placebo (n=13) and in the active (n=16, treated with caffeine/ephedrine mixture) groups. +P<0.05, *P<0.01 placebo vs active; #P<0.05, ##P<0.01 vs week 0 (ANOVA).

Figure 3
figure3

Change in LBM by week 20 in the placebo (n=13) and in the active (n=16, treated with caffeine/ephedrine mixture) groups (ANOVA).

Blood glucose, plasma insulin, total cholesterol, HDL-cholesterol, ApoA1 levels and thyroid hormone plasma concentrations did not change during the trial period in either group (Table 2). The plasma triglyceride and ApoB plasma concentrations of the active group were significantly lower than those of the placebo group. The decline of plasma ApoB concentration in the active group was significant by week 20 (Table 2). Standard safety parameters (haemoglobin, haematocrit, white blood cell and platelet count, ASAT, LDH, bilirubin, ALP, serum albumin and creatinine) were in the normal range in all patients at baseline and remained there at weeks 8 and 20. Urine was negative for glucose and albumin in all patients at all time points.

Blood pressure and heart rate values showed no significant changes during the trial in either group (Table 3). The expected adaptive decrease in the RMR did not occur in the active group in spite of the considerable weight loss (Table 4). Baseline physical fitness parameters of the two groups were comparable and no deterioration or significant improvement was observed in them during the 20-week treatment period (Table 5).

Table 5 Physical fitness parameters at the beginning and at the end of the trial in the placebo (n=13) and active (n=16) groups (mean±s.d.)

With respect to side effects, 11 and 10 patients reported some kind of side effects from the PL and CE groups, respectively. The total numbers of side effects reported were 31 and 36, of which 26 and 31 were considered by the blinded investigator to be related to treatment in the PL and CE groups, respectively. The distribution of side effect by signs and by time is shown in Tables 6 and 7. It is worth mentioning that side effects were more frequent at the beginning of the treatment in the active group than in the placebo group and interestingly they were more frequent in the follow-up period as compared to the beginning of the treatment in the placebo group (Table 7).

Table 6 The number of different side effects in the two treatment groups
Table 7 Distribution of side effects by time

The side effects were transient and graded as mild to moderate in the majority of the cases. Side effects were graded as severe on six occasions (PL: 5; CE: 1), namely insomnia in three (PL: 2; CE: 1), palpitation in one (PL) and other (excessive sweating and diarrhoea) in two (PL) occasions. Due to the side effects the dose of the drug was reduced transiently in three cases (2 active, 1 placebo). No serious adverse reactions were encountered in the trial.

The number of reported withdrawal symptoms (sweating, palpitation, tremor, nervousness, vomiting, diarrhoea, insomnia and poor general state of health), checked on the first, third and fifth day of the weaning period, were not different in the PL and CE groups, that is 24 and 25, 23 and 25, 17 and 24, respectively. Placebo patients reported withdrawal symptoms as severe on 16 occasions, and active patients on 19 occasions.

Discussion

The results of the 20 week randomized double-blind trial indicate that the +caffeine taken orally three times a day as an adjuvant to a moderately low energy diet spectacularly improves weight loss (7.9±6.0 vs 0.5±4.3 kg). The considerable weight loss observed in the CE group was due to the decrease of body fat, while LBM was fairly well preserved. These observations confirm the previous findings in obese adults.4,10,11

Some of the well-known cardiovascular risk factors also improved in the active group. The plasma triglyceride and apolipoprotein B plasma concentrations in the active group were significantly lower than that of the placebo group at the 20th week. The decline of plasma ApoB concentration in the active group was significant by week 20. HDL-cholesterol plasma concentrations did not fall in the active group in spite of the considerable weight loss. The ephedrine +caffeine treatment did not cause any change in the systolic and diastolic blood pressure values of the subjects. Ephedrine+caffeine mixture promotes weight reduction by a transient decrease in appetite and by increasing RMR (preventing the decrease in RMR induced by weight loss).12,13 We attempted to evaluate the changes in energy intake of subjects during the treatment but serious underreporting (daily energy intake <RMR) was so frequent that the results of dietary reports could not be used. The significant fall of RMR that generally follows weight reduction was not observed in the active group, probably due to the sympathomimetic action of the ephedrine/caffeine mixture. The cardiopulmonary responses of the subjects to stress testing were not affected by 20 weeks of treatment, supporting the observations of Stich et al14 made in adults after 3 days of CE treatment.

The total number of side effects were not different in the CE group as compared to the PL group, however, side effects were more frequent at the beginning of the treatment in the former than in the latter group. The side effects were transient and graded as mild to moderate in the majority of the cases. Severe side effects were reported mainly in the PL group. The number of reported withdrawal symptoms were not different in the PL and CE groups.

In conclusion, the major finding of this study indicates that the combination of CE taken orally improves weight loss in adolescents. The side effects are generally mild and temporary. No clinically important side effects or withdrawal symptoms were observed.

Since the number of children included into the study was small and the duration of the treatment was relatively short, further investigations on a larger number of subjects, with longer treatment period are needed before the use of the C+E mixture in obese adolescents could be recommended.

To the best of our knowledge, the present study is the first randomized clinical trial on a currently available antiobesity drug in adolescents or children.

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Acknowledgements

The project was supported by NYCOMED DAK Pharmaceutical Company, Roskilde, Denmark, and in part by the Hungarian National Research Fund (OTKA T-026663 to DM) and by the Hungarian Ministry of Welfare (081/1996 to DM).

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Molnár, D., Török, K., Erhardt, E. et al. Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double-blind placebo-controlled pilot study in adolescents. Int J Obes 24, 1573–1578 (2000). https://doi.org/10.1038/sj.ijo.0801433

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Keywords

  • obesity
  • ephedrine
  • caffeine

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