Table II.

Randomized controlled trials of efficacy of naltrexone for weight loss in adult patients

Author (year), journal, title	Quality	No. of patients	Inclusion criteria	Intervention Comparator	Active N Age % female	Primary outcome	Efficacy assessment Effect size – ES (95% CI)	Safety
Halseth A et al. (2017) Journal: Obesity Title: Method of use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity	IF: 3.873 (2015) Category of evidence: Ib Jadad: 4/5 Cochrane risk of bias: low risk of bias	N = 242	Adult male and female subjects, aged 18 to 60 years, had either obesity (body mass index [BMI] 30–45 kg/m2) or overweight (BMI 27–45 kg/m2) with dyslipidaemia and/or controlled hypertension	Naltrexone/bupropion (NB) 32 mg/day / 360 mg/day for 26 weeks and commercially available comprehensive lifestyle intervention (CLI) programme Usual care (diet and exercise education and recommendations from the study site)	N = 153 Age = 46.1 ±9.66 Female = 81.7%	Percent change in body weight from baseline (day 1) to week 26	At week 26 NB + CLI subjects lost significantly more weight than usual care subjects (8.52% difference; p < 0.0001)	The most frequent adverse events (AEs) that led to discontinuation of NB for the two groups combined included nausea (7.0%), anxiety (2.1%), headache (1.7%), dizziness (1.2%), and insomnia (1.2%)
Nissen SE et al. (2016) Journal: JAMA Title: Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial	IF: 7.48 (2015) Category of evidence: Ib Jadad: 4/5 Cochrane risk of bias: low risk of bias	N = 8910	Patients aged 50 years or older (women) or 45 years or older (men), BMI 27–50 kg/m2, and having a waist circumference of 88 cm or more (women) or 102 cm or more (men)	Naltrexone/bupropion 32 mg/day / 360 mg/day Placebo	N = 4456 Age = 61.1 ±7.27 Female = 54.7%	Time from treatment randomization to the first confirmed occurrence of: major adverse cardiovascular events (MACE)	Time to first MACE, occurred in 192 patients, 102 (2.3%) in the placebo group and 90 (2.0%) in the naltrexone/bupropion group (HR = 0.88; 99.7% CI: 0.57–1.34)	Adverse event occurred in 543 patients (5.2%)
						Defined as cardiovascular death	The components of the primary composite outcome included cardiovascular death in 34 placebo-treated patients (0.8%) and 17 naltrexone/bupropion-treated patients (0.4%; HR = 0.50; 99.7% CI: 0.21–1.19)
						Nonfat stroke	Nonfatal stroke occurred in 19 patients (0.4%) in the placebo group and 21 (0.5%) in the naltrexone/bupropion group (HR = 1.10; 99.7% CI: 0.44–2.78)
						Nonfat myocardial infarction	Nonfatal myocardial infarction occurred in 54 patients (1.2%) in the placebo group and 54 (1.2%) in the naltrexone/bupropion group (HR = 1.00; 99.7% CI: 0.57–1.75)
Kolotkin RL et al. (2015) Journal: Clinical Obesity Title: Patient-reported quality of life in a randomized placebo-controlled trial of naltrexone/bupropion for obesity	IF: no data (2015) Category of evidence: Ib Jadad: 4/5 Cochrane risk of bias: unclear risk of bias	N = 3362	Patients with BMI 30–45 kg/m2, or a BMI 27–45 kg/m2 and controlled hypertension and/or dyslipidaemia	Naltrexone/bupropion 32 mg/day / 360 mg/day Placebo	N = 2043 Age = 46 ±11 Female = 81%	Changes at 56 weeks in quality of life, measured by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire	Improvements in IWQOL-Lite Total Score were greater in subjects treated with NB32 (11.9 points [SE = 0.3]) vs. placebo (8.2 points [SE = 0.3]; p < 0.001), corresponding to weight reductions of 7.0% (SE = 0.2) and 2.3% (SE = 0.2)	Adverse events: the most frequently reported being nausea, constipation, headache and vomiting
Mason AE et al. (2015) Journal: Apetite Title: Acute responses to opioidergic blockade as a biomarker of hedonic eating among obese women enrolled in a mindfulness-based weight loss intervention trial	IF: 1.47 (2016) Category of evidence: Ib Jadad: 2/5 Cochrane risk of bias: unclear risk of bias	N = 88	BMI of 30–45.9 kg/m2, abdominal obesity (female waist circumference > 88 cm), and age 18 or older	All participants ingested the placebo and the 50 mg naltrexone	N = 88 Age = 46.7 ±13.2 Female = 100%	Cortisol responses	Cortisol levels at 1 PM on the placebo day (median = 4.35) and naltrexone day (median = 3.70) were not statistically significantly different, Z = –1.29, p = 0.20 Cortisol levels at 3 PM on the naltrexone day (median = 3.87) were higher than those on the placebo day (median = 2.19), Z = 4.25, p < 0.001 Similarly, cortisol levels at 4 PM on the naltrexone day (median = 4.63) were higher than those on the placebo day (median = 1.95), Z = 5.70, p < 0.001	Adverse event: nausea
						Nausea responses	Significantly more women reported experiencing nausea on the naltrexone day (n = 38, 43.2%) than on the placebo day (n = 15, 17.0%; p < 0.001)
Tek C et al. (2014) Journal: J Clin Psychopharmacol Title: A randomized, double-blind, placebo-controlled pilot study of naltrexone to counteract antipsychotic-associated weight gain: proof of concept	IF: 2.38 (2014) Category of evidence: Ib Jadad: 3/5 Cochrane risk of bias: unclear risk of bias	N = 24	Overweight women between the ages of 18–70 who met DSM-IV criteria for schizophrenia or schizoaffective disorder, based on SCID	Naltrexone (NTX) 25 mg/day Placebo	N = 11 Age = 50.0 ±9.6 Female = 100%	Change in body weight from baseline	Patients in the NTX group had significant weight loss (–3.40 kg) compared with weight gain (+1.37 kg) in the patients in the placebo group The subjects assigned to NTX had a significant reduction in BMI (–1.37; CI: –2.054 to –0.68; F = 15.86; p = 0.001) vs. that of PLA (0.57; CI: –0.79 to –1.22) after the intervention	The medication did not produce any adverse change in psychiatric symptoms and was well tolerated
Taveira TH et al. (2014) Journal: J Psychopharmacol Title: The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: a randomized double-blind placebo-controlled pilot study	IF: 2.79 (2015) Category of evidence: Ib Jadad: 3/5 Cochrane risk of bias: unclear risk of bias	N = 30	Patients with schizophrenia or schizoaffective disorder on a stable dose of olanzapine (OLZ) (≥ 5 mg/day and ≤ 30 mg/day), BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 plus one symptom of metabolic syndrome (i.e. hypertension, dyslipidaemia or fasting blood) glucose > 125 mg/dl	Naltrexone (50 mg/day) Placebo	N = 14 Age = 43.6 ±11.2 Female = 37.5%	The change in BMI at 12 weeks	No significant change in BMI. However, the OLZ + NTX group displayed a significant decrease in fat and increase in fat-free mass. The group-by-time interaction showed a significant increase in fat-free mass in the NTX group over time (p = 0.03) without significant group (p = 0.22) or time effects (p = 0.20)	No participants reported that they discontinued the study due to adverse side effects
Hollander P et al. (2013) Journal: Diabetes Care Title: Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycaemic parameters in overweight and obese patients with type 2 diabetes	IF: 5.00 (2013) Category of evidence: Ib Jadad: 4/5 Cochrane risk of bias: low risk of bias	N = 505	Smoking or non-smoking men and women with type 2 diabetes, aged 18–70 years, with a BMI ≥ 27 kg/m2 and ≤ 45 kg/m2, HbA1c between 7% (53 mmol/mol) and 10% (86 mmol/mol), and fasting blood glucose < 270 mg/dl	Naltrexone/bupropion 32 mg/day / 360 mg/day Placebo	N = 335 Age = 54.0 ±9.1 Female = 58.2%	Percent change in body weight from baseline to week 56 compared with placebo	NB resulted in significantly greater weight reduction (–5.0 vs. –1.8%; p < 0.001) and compared with placebo	Adverse events: nausea (withdrawal 9.6%), constipation, vomiting, diarrhoea Incidence of serious adverse events was low (3.9% for NB and 4.7% for placebo)
						Percentage of participants achieving ≥ 5% reduction in body weight from baseline to week 56 compared with placebo	NB resulted in significantly greater weight proportion of patients achieving ≥ 5% weight loss (44.5 vs. 18.9%, p < 0.001)
Apovian CM et al. (2013) Journal: Obesity (Silver Spring) Title: A Randomized, Phase 3 Trial of Naltrexone SR/Bupropion SR on Weight and Obesity-related Risk Factors (COR-II)	IF: 5.18 (2013) Category of evidence: Ib Jadad: 5/5 Cochrane risk of bias: low risk of bias	N = 1496	Patients with BMI 30–45 kg/m2, or a BMI 27–45 kg/m2 and controlled hypertension and/or dyslipidaemia	32 mg/day naltrexone SR + 360 mg/day bupropion SR (NB32) Placebo	N=1001 Age= 44.3 ±11.2 Female = 84.6%	Percent weight change	Significantly (p < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (–6.5% vs. –1.9%) and week 56 (–6.4% vs. –1.2%)	Most common adverse event: nausea Discontinuations in both groups during the first 8 weeks of the study, with more discontinuations, particularly because of AEs, occurring with NB
						Proportion achieving ≥ 5% weight loss at week 28	More NB32-treated participants (p < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%)
Wadden TA et al. (2011) Journal: Obesity (Silver Spring) Title: Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behaviour modification: the COR-BMOD trial	IF: 4.41 (2011) Category of evidence : Ib Jadad: 5/5 Cochrane risk of bias: low risk of bias	N = 793	Patients 18–65 years of age who had a BMI of 30–45 kg/m2, or a BMI of 27–45 kg/m2 in the presence of controlled hypertension and/or dyslipidaemia	32 mg/day naltrexone SR + 360 mg/day bupropion SR (NB32) Placebo	N = 591 Age = 45.9 ±10.4 Female = 89.3%	Percent weight change at week 56	At week 56, participants treated with placebo + behavior modification (BMOD) lost 5.1 ±0.6% of initial weight, compared with a significantly (p < 0.001) greater 9.3 ±0.4% for those who received NB32 + BMOD	Presents AEs that occurred in ≥ 5% of participants in either treatment group and with greater incidence in NB32 + BMOD than in placebo + BMOD Nausea in 34.1% of participants treated by NB32 + BMOD reporting at least one event, compared to 10.5% for placebo + BMOD (p < 0.001) Others: constipation, dizziness, dry mouth, tremor, abdominal pain, and tinnitus occurred more often in the NB32 + BMOD group than in placebo + BMOD
						Proportion achieving ≥ 5% weight loss at week 56	The proportions of participants who achieved ≥ 5%, ≥ 10%, and ≥ 15% reductions in baseline weight were greater with NB32 + BMOD than with placebo + BMOD (p < 0.001)
Greenway FL et al. (2011) Journal: Lancet Title: 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	IF = 8.56 (2010) Category of evidence: Ib Jadad: 5/5 Cochrane risk of bias: low risk of bias	N = 1742	Men and women aged 18–65 years who had a BMI of 30–45 kg/m2 and uncomplicated obesity or BMI 27–45 kg/m2 with dyslipidaemia or hypertension	32 mg/day naltrexone SR + 360 mg/day bupropion SR (NB32) 16 mg/day naltrexone SR + 360 mg/day bupropion SR (NB32) Placebo	n = 583 Age = 44.4 ±11.3 Female = 85% n = 578 Age = 44.4 ±11.1 Female = 85%	Percent weight change at week 56	Mean change in body weight was –1.3% (SE = 0.3) in the placebo group, –6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p < 0.0001 vs. placebo) and –5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p < 0.0001 vs. placebo)	Nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]) Headache, constipation, dizziness, vomiting, dry mouth were also more frequent in the naltrexone plus bupropion groups than placebo
						Proportion achieving ≥ 5% weight loss at week 56	84 (16%) participants in placebo had a decrease in body weight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p < 0.0001 vs. placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p < 0.0001 vs. placebo)