Thus, future studies should uncover the participation of these neuronal populations and associated brain circuits, in the mechanism of action of appetite suppressants and its combinations. Although the roles of DA and 5-HT in the ventral striatum are well established for feeding and some neuropsychiatric maladies such as addiction and depression, respectively Zangen et al.
Thus, each appetite suppressant produces a specific neurochemical profile that most likely determines its desirable pharmacological effects but also its adverse side-effects. Previous studies support the idea that DA releasing appetite suppressants e. Thus, we rationalized how Phen could induce the strongest modulations either alone or in combination. Importantly, we uncovered that a DA releasing agent and a 5-HT precursor both recruited largely overlapping neuronal ensembles, suggesting that NAcSh neurons received convergent influence of DA and 5-HT afferents.
In summary, we provide preclinical evidence, in rats, supporting the use of a triple drug combination for the treatment of obesity, while partially reducing undesirable psychomotor side-effects of Phen. The datasets generated for this study are available on request to the corresponding author. CP analyzed data and made figures. RG wrote the article.
Productos Medix SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
A special thanks to Gadagkar, S. R for help in the computation of the effective dose of drugs and to Esmeralda Fonseca and Andrew Harley for valuable comments on an early version of this manuscript. We thank professor Sid A. Supplementary Figure 1 Carbidopa alone prevented body weight gain.
Rats treated with CB maintained the same body weight relative to their initial weight in BL. The panel at right indicates the average weight change in g. Supplementary Figure 2 Behavioral states induced by appetite suppressants. Percentage of cumulative time spent in each of the following behavioral states: sleeping, quite awake, and moving for 5 min. Measurements were made around 1 h after the onset of drug administration.
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Contrave is indicated for long-term use while phentermine is indicated for short-term use. Phentermine usually causes tolerance in several weeks, at which point it should be stopped. Drug selection is based on a variety of factors, such as other medical conditions, anticipated side effects and drug interactions, and insurance coverage. For example, a patient who does not have insurance coverage may be better suited for phentermine, which is relatively inexpensive.
On the other hand, Contrave may be a better choice in a patient with a history of substance use disorder. Either way, diet, and exercise are important to help with weight loss in addition to medication. Your healthcare professional can determine which, if any, drug is appropriate for you, taking into account your medical conditions, history, and drugs you take that could interact with Contrave or phentermine.
Contrave is sometimes covered by insurance plans but is generally not covered by Medicare prescription plans. A free SingleCare card can lower the price substantially. Insurance and Medicare prescription plans do not usually cover phentermine. Because insurance plans vary and can change, it is best to contact your insurance provider for up-to-date coverage information. The most common possible side effects of Contrave are:.
Common side effects of phentermine include :. Report side effects or any changes that concern you to your doctor. Allergic reactions are rare, but if you experience symptoms of an allergic reaction such as hives, difficulty breathing, or swelling around the face, lips, tongue, or throat, get emergency medical help right away.
This is not a full list of side effects, and other adverse effects may occur. Consult your healthcare professional for a full list of side effects. Before taking Contrave or phentermine, tell your doctor about all of the medications you take, including prescription drugs, over-the-counter medicines, and vitamins or supplements.
Your doctor will need this information to determine if Contrave or phentermine is compatible with the other medications you take. With either Contrave or phentermine, people taking insulin or oral medications for diabetes may need dosage adjustments as they lose weight. This is not a full list of drug interactions. Consult your healthcare provider for a full list of drug interactions.
Before taking a weight-loss medication, talk to your doctor about all of the medical conditions you have, and all of the medications you take, so your doctor can determine if a weight-loss medication is safe for you. When you fill your prescription for Contrave or phentermine, you will receive a medication guide or patient leaflet that contains important information and warnings.
Read all of the information carefully and ask your healthcare provider if you have any questions or concerns. If you take Contrave or phentermine, take as prescribed by your doctor. Follow dosing instructions closely. Do not take more medication than your doctor tells you to. Do not take Contrave or phentermine with other weight-loss drugs, including prescription drugs, OTC medicines, vitamins, or supplements. With either drug, weight loss can result in low blood sugar.
Blood glucose levels should be monitored. Report low blood sugar to your healthcare provider. For Contrave or phentermine, keep the drug in its labeled container, securely away from children or pets. Do not drive or operate machinery until you know how Contrave or phentermine affects you. Do not drink alcohol with Contrave or phentermine. Contrave has a black box warning. This is the strongest warning required by the FDA.
The warning states that although Contrave contains bupropion, an antidepressant, Contrave is not approved to treat depression or other psychiatric disorders.
Antidepressants cause an increased risk of suicidal thoughts and behavior in children, adolescents, and young adults up to age Anyone who takes Contrave should be closely monitored for suicidal thoughts and behaviors. Two trials 49 , 50 provided information on weight regain after discontinuing sibutramine therapy.
The second phase of a randomized, double-blind, crossover study by Fanghanel et al 50 provided data on weight regain at 6 months. In the second 6-month phase of the trial, 40 participants crossed over to placebo and regained 3. The placebo arm of the 2-year weight maintenance trial by James et al 49 provides data on weight regain at 18 months.
During the weight maintenance phase, participants received placebo for 18 months and regained 6. No study participants died during the follow-up of 44 eligible trials. We identified several potential causes of the heterogeneity. Given the heterogeneity and the missing data, we could not pool the blood pressure results for meta-analysis.
The only 1-year trial 42 that met these criteria was conducted in adults with type 2 diabetes mellitus who were treated with metformin hydrochloride. Participants in this trial were allowed to continue their antihypertensive treatments if the dose had been stable for at least 3 months.
Changes in antihypertensive treatments during the trial were not reported. The effects of sibutramine on systolic and diastolic blood pressure in the high-quality 3- and 6-month trials 24 , 28 , 31 , 46 were highly varied, and ranged from net reductions to net increases Table 2.
The summary mean difference in heart rate was 3. The ranges of heart rate effects are also presented in Table 2. We identified 2 trials 28 , 52 that were specifically designed to evaluate the effects of sibutramine on heart valve function. The largest and longest study 52 obtained a single echocardiogram for participants after an average of 7. No trial provided a detailed assessment of the types of, dose of, and changes in lipid-lowering medications.
Again, only one high-quality 1-year trial 42 was identified. This trial also reported no effect of sibutramine on total cholesterol and low-density lipoprotein cholesterol levels when compared with placebo. Sibutramine plus lifestyle modification is more effective than placebo plus lifestyle modification in promoting weight loss at 3, 6, and 12 months among healthy overweight and obese adults and adults with type 2 diabetes mellitus, hypertension, or hyperlipidemia.
Adults who continue sibutramine therapy for 2 years may maintain their weight loss better than adults taking placebo. One of our goals was to estimate the cardiovascular and metabolic effects of sibutramine. The trials we identified were not designed and powered to detect changes in these outcomes. Among those trials that did measure cardiovascular and metabolic outcomes, the results were inconsistently reported, and we could not exclude confounding due to concomitant changes in antihypertensive, lipid-lowering, and diabetes mellitus medications in most of the trials.
Given these limitations, the highest-quality trials suggest that weight loss with sibutramine is associated with modest increases in heart rate and blood pressure, small improvements in high-density lipoprotein cholesterol and triglycerides levels, and, among diabetic patients, small improvements in glycemic control. We found no direct evidence that sibutramine prevents or reduces obesity-associated morbidity or mortality.
Without direct evidence of morbidity and mortality reductions from weight loss drugs, authors 53 , 54 in this field have traditionally cited epidemiological evidence of the associations between weight loss, mortality, and cardiovascular events in support of the potential for long-term benefits with these agents. While it is "highly probable that weight loss that reduces blood pressure and cholesterol will reduce the number of deaths from heart disease and stroke," 55 p14 our review suggests that weight loss with sibutramine is associated with both positive and negative changes in cardiovascular and metabolic risk factors.
Thus, we cannot exclude the possibility that these changes will have important long-term effects on cardiovascular disease risk that enhance, diminish, or reverse the health benefits that result from modest weight loss. In December , the European Committee for Proprietary Medicinal Products concluded that the risk-benefit profile of sibutramine was positive. However, the European Committee for Proprietary Medicinal Products could not exclude the possibility that sibutramine may have a relevant cardiovascular risk.
Our review suggests that the effects of sibutramine on cardiovascular and metabolic outcomes are not entirely positive. While our review is limited to published clinical trials and unpublished data that individual researchers would share with us, the European Committee for Proprietary Medicinal Products has access to confidential industry data. We were unable to obtain additional unpublished data from the manufacturer, Abbott Laboratories.
Given the limitations of the available data on secondary outcomes, we conclude that there is insufficient evidence to accurately determine the long-term risk-benefit profile for sibutramine. Some experts 57 suggest that sibutramine should be used as a short-term aid to long-term lifestyle modifications that promote weight loss and weight maintenance.
We did not identify any evidence to support this theoretical use. Until larger, longer-term, and higher-quality randomized trials of the effects of sibutramine on cardiovascular and metabolic outcomes are conducted, the risk-benefit ratio of this drug will remain unclear. Future trials should be designed and powered to detect differences in incident diabetes mellitus, cardiovascular disease, and valvular disease. Changes in blood pressure, lipid levels, glycemic control, and quality-of-life measures should be reported for all sibutramine trials.
Concomitant changes in antihypertensive, lipid-lowering, and diabetic medications should be recorded in greater detail. Trials should also devote more effort to obtaining complete follow-up of study participants. While clinicians wait for the outcome of this trial, a systematic review of individual-level data may shed additional light on these issues. Our findings for weight loss are consistent with prior reviews 13 of this literature; however, previous reviews did not evaluate unpublished evidence, provide pooled estimates of effect at 1 year, or comment on weight regain and weight maintenance.
There are several limitations to our analysis. The trials we reviewed had high average scores 3 points on the quality scale of Jadad et al 15 ; however, several methodological and quality issues were identified. These trials were small—only one trial enrolled more than patients.
Kjaergard et al 16 demonstrated that trials of this size that did not report adequate generation and concealment of randomized treatment allocation frequently presented biased effect estimates. Although our sensitivity analyses were unable to detect such bias, only 4 trials reported proper allocation methods. Most of the trials we reviewed had significant problems with participants who were lost to follow-up, making the safety and efficacy results difficult to interpret.
These trials either ignored missing data in their analyses by analyzing completers only or used the LOCF method of analysis despite its known weaknesses.
In general, authors and journal editors have not paid enough attention to missing data in sibutramine trials. Standardized analysis and reporting of efficacy and safety data would facilitate cross-study comparisons to help guide clinicians as they treat their obese patients. Despite our attempts to include published and unpublished trials in our analyses, we detected evidence of publication bias among the to week trials. This finding is consistent with previous reports 59 from the obesity literature.
Subgroup A provides our best estimate of the efficacy of sibutramine at 16 to 24 weeks because it is composed of the highest-quality trials at this treatment duration.
We did not find evidence of publication bias at other treatment durations; however, the numbers of trials in these analyses were small, and we may have lacked power to detect significant bias. In summary, the results of our study indicate that sibutramine is more effective than placebo in achieving weight loss in obese adults who receive lifestyle modifications. Our findings were consistent across trials of different duration and across patient groups with various obesity-related comorbidities, including diabetes mellitus, hypertension, and hyperlipidemia.
We found evidence that discontinuing sibutramine leads to weight regain. Weight loss with sibutramine was associated with increased systolic and diastolic blood pressures; however, these and other important cardiovascular and metabolic outcomes were inconsistently reported. Thus, we conclude that there is insufficient evidence to accurately determine the risk-benefit profile for sibutramine. Despite the presence of 44 randomized controlled trials of sibutramine for weight loss, there continues to be a need for high-quality long-term safety and outcomes data to inform clinical decisions.
Corresponding author and reprints: David E. Tambascia, MD, for providing unpublished data. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. Figure 1. View Large Download. Table 1.
Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Am J Clin Nutr.
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