References
- Papers of particular note have been highlighted as:
**Of interest
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- Finkelstein EA, et al. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood). 2009;28(5):w822–31.
- Reece AS. Hypothalamic opioid-melanocortin appetitive balance and addictive craving. Med Hypotheses. 2011;76(1):132–137.
- Krude H, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155–157.
- Greenway FL, et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2009;17(1):30–39.
**The first Phase II clinical trial assessing efficacy and safety of NB compared to placebo
- Caixas A, et al. Naltrexone sustained-release/bupropion sustained-release for the management of obesity: review of the data to date. Drug Des Devel Ther. 2014;8:1419–1427.
- Pennock RL, Hentges ST. Differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating hypothalamic proopiomelanocortin neurons. J Neurosci. 2011;31(1):281–288.
- Cowley MA, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480–484.
- Ellacott KL, Cone RD. The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. Recent Prog Horm Res. 2004;59:395–408.
- Huszar D, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131–141.
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- Yaswen L, et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. 1999;5(9):1066–1070.
- Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21–34.
- Rodgers RJ, Tschop MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Model Mech. 2012;5(5):621–626.
- Pucci A, Finer N. New medications for treatment of obesity: metabolic and cardiovascular effects. Can J Cardiol. 2015;31(2):142–152.
- Nau JY. Mysimba, an American appetite suppressant and the logic of the single European market. Rev Med Suisse. 2015;11(470):890–891.
- Ascher JA, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395–401.
- Billes SK, Cowley MA. Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice. Neuropsychopharmacology. 2007;32(4):822–834.
- Pijl H. Reduced dopaminergic tone in hypothalamic neural circuits: expression of a “thrifty” genotype underlying the metabolic syndrome? Eur J Pharmacol. 2003;480(1–3):125–131.
- Thomas SA, Palmiter RD. Disruption of the dopamine beta-hydroxylase gene in mice suggests roles for norepinephrine in motor function, learning, and memory. Behav Neurosci. 1997;111(3):579–589.
- Yang ZJ, et al. Bilateral hypothalamic dopamine infusion in male Zucker rat suppresses feeding due to reduced meal size. Pharmacol Biochem Behav. 1997;58(3):631–635.
- Wellman PJ. Modulation of eating by central catecholamine systems. Curr Drug Targets. 2005;6(2):191–199.
- Verpeut JL, Bello NT. Drug safety evaluation of naltrexone/bupropion for the treatment of obesity. Expert Opin Drug Saf. 2014;13(6):831–841.
- Settle EC, et al. Safety profile of sustained-release bupropion in depression: results of three clinical trials. Clin Ther. 1999;21(3):454–463.
- Jain AK, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res. 2002;10(10):1049–1056.
- Anderson JW, et al. Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial. Obes Res. 2002;10(7):633–641.
- Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101(4):491–503.
- Anton RF. Naltrexone for the management of alcohol dependence. N Engl J Med. 2008;359(7):715–721.
- Gosnell BA, Levine AS. Reward systems and food intake: role of opioids. Int J Obes (Lond). 2009;33(Suppl 2):S54–8.
- Obese FY, et al. Long-term feed intake regulation in sheep is mediated by opioid receptors. J Anim Sci. 2007;85(1):111–117.
- Brown DR, Holtzman SG. Suppression of deprivation-induced food and water intake in rats and mice by naloxone. Pharmacol Biochem Behav. 1979;11(5):567–573.
- Holtzman SG. Behavioral effects of separate and combined administration of naloxone and d-amphetamine. J Pharmacol Exp Ther. 1974;189(1):51–60.
- Kurbanov DB, et al. Effects of naltrexone on food intake and body weight gain in olanzapine-treated rats. J Psychopharmacol. 2012;26(9):1244–1251.
- Spiegel TA, et al. Effect of naltrexone on food intake, hunger, and satiety in obese men. Physiol Behav. 1987;40(2):135–141.
- Atkinson RL, et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985;38(4):419–422.
- Maggio CA, et al. Naltrexone and human eating behavior: a dose-ranging inpatient trial in moderately obese men. Brain Res Bull. 1985;14(6):657–661.
- Malcolm R, et al. A controlled trial of naltrexone in obese humans. Int J Obes. 1985;9(5):347–353.
- Greenway FL, et al. Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. J Clin Endocrinol Metab. 2009;94(12):4898–4906.
**A larger Phase II clinical trial assessing efficacy and safety of NB compared to placebo
- Greenway FL, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595–605.
**The COR-I trial: first Phase III clinical trial assessing clinical efficacy of NB compared to placebo.
- Apovian CM, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013;21(5):935–943.
**The COR-II trial: Phase III clinical trial assessing clinical efficacy of NB compared to placebo.
- Wadden TA, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring). 2011;19(1):110–120.
**The COR-BMOD trial: Phase III clinical trial assessing clinical efficacy of NB in association with behavior modification.
- Hollander P, et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022–4029.
**The COR-D trial: Phase III clinical trial assessing clinical efficacy of NB in diabetes mellitus patients.
- Contrave [package insert]. Deerfield (IL): Takeda Pharmaceuticals America, Inc; 2014.
- Apovian CM, Louis Arrone, Powell AG. Clinical management of obesity. 1st ed. West Islip (NY): Professional Communications, Inc; 2015.
- Cardiovascular outcomes study of Naltrexone SR/Bupropion SR in overweight and obese subjects with cardiovascular risk factors (The Light Study) [Internet]. [cited 2015 Jul 1]. 2012. Available from: https://clinicaltrials.gov/ct2/show/NCT01601704.
- News, C.C. Clinical trial testing safety of obesity drug contrave halted; 50 percent interim data released by the study’s executive committee [Internet]. [cited 2015 Aug 25]. Cleveland (OH): Cleveland Clinic Newsroom; 2015 [ updated 2015]. Available from: http://my.clevelandclinic.org/about-cleveland-clinic/newsroom/releases-videos-newsletters/2015-5-12-clinical-trial-testing-safety-of-obesity-drug-contrave-halted.
- Orexigen Therapeutics, I. Orexigen therapeutics provides statement on termination of the light study and updates on contrave collaboration with takeda pharmaceuticals [Internet]. [cited 2015 Jul 1]. San Diego (CA): Orexigen Therapeutics, Inc.; 2015 [ updated 2015]; Available from: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=2047312.
- Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005;82(1 Suppl):222S–225S.
- Sjostrom L, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741–752.
- Sjostrom L, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307(1):56–65.
- Kashyap SR, et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care. 2013;36(8):2175–2182.