How does Contrave (naltrexone-bupropion Extended Release (ER)) work for weight loss in an adult patient with a history of fibromyalgia or Complex Regional Pain Syndrome (CRPS)?

How Contrave Works for Weight Loss

Contrave (naltrexone-bupropion ER) works through a synergistic dual mechanism targeting the hypothalamic appetite control center: bupropion activates pro-opiomelanocortin (POMC) neurons that release appetite-suppressing signals, while naltrexone blocks the auto-inhibitory feedback that would normally dampen this effect, resulting in sustained appetite reduction and weight loss. 1

Mechanism of Action

Central Nervous System Pathway

• Bupropion is a dopamine/norepinephrine reuptake inhibitor that activates anorexigenic POMC neurons in the arcuate nucleus of the hypothalamus 1
• This activation causes release of alpha-melanocyte-stimulating hormone (α-MSH), a potent appetite-suppressing neuropeptide that projects to other hypothalamic areas controlling feeding and body weight 1
• However, bupropion alone has weak anorectic effects because β-endorphin (released by the same POMC neurons) has auto-inhibitory activity on these cells 1

Synergistic Enhancement

• Naltrexone is an opioid receptor antagonist that blocks the auto-inhibitory effect of β-endorphin on POMC neurons 1
• By removing this negative feedback, naltrexone potentiates bupropion's appetite-suppressing effects, creating a synergistic combination that produces greater weight loss than either drug alone 1, 2
• The combination also modulates hedonic eating (reward-driven eating) through increased dopamine levels and opioid receptor antagonism 1

Clinical Efficacy

Weight Loss Outcomes

• Across four Phase III trials (COR-I, COR-II, COR-BMOD, COR-DM) involving 4,536 adults, naltrexone-bupropion ER produced average weight loss of 11-22 lbs (5-9 kg) over 52-56 weeks 3, 4
• The medication demonstrated statistically significant and clinically meaningful weight loss compared to placebo in all trials 3, 4
• Significantly more patients achieved ≥5% and ≥10% body weight reduction compared to placebo 4

Cardiometabolic Benefits

• Treatment resulted in significant improvements in cardiometabolic risk factors including lipid profiles and blood pressure 3, 4
• In patients with type 2 diabetes, greater improvements in glycated hemoglobin (HbA1c) levels were observed versus placebo 4

Special Considerations for Fibromyalgia and CRPS Patients

Potential Benefits

• Bupropion's norepinephrine and dopamine activity may provide additional benefit for patients with fibromyalgia or CRPS, as these conditions often involve central pain processing abnormalities 1
• The medication addresses both weight management and may improve energy levels and reduce apathy, which are common in chronic pain conditions 5

Critical Contraindication

• Naltrexone blocks opioid receptors, making Contrave absolutely contraindicated in patients taking chronic opioid therapy for pain management 1, 6
• The medication must be discontinued before any procedures requiring opioid analgesia (such as endoscopies with fentanyl) 6
• Confirm the patient is not currently taking opioid medications before initiating naltrexone-bupropion 5, 6

Seizure Risk Considerations

• Bupropion lowers seizure threshold and should be avoided in patients with seizure disorders, eating disorders, or conditions predisposing to seizures 1, 5, 6
• Use extreme caution if the patient has a history of head trauma, brain tumor, or stroke 5
• Avoid in patients with abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 5, 6

Dosing and Administration

Titration Schedule

• Week 1: 8 mg naltrexone/90 mg bupropion once daily in the morning 1, 5
• Week 2: 8/90 mg twice daily 1, 5
• Week 3: 16/180 mg in the morning and 8/90 mg in the evening 1, 5
• Week 4 and beyond: 16/180 mg twice daily (maintenance dose = 32/360 mg total daily) 1, 5
• The second dose should not be taken late in the day to minimize insomnia risk 1, 5, 6

Dose Adjustments

• Moderate to severe renal impairment: Reduce total daily dose by half (1 tablet twice daily); avoid in end-stage renal disease 1, 5, 6
• Moderate to severe hepatic impairment: Do not exceed 1 tablet daily (maximum 150 mg bupropion) 1, 5, 6

Efficacy Assessment and Discontinuation

• Discontinue the medication if the patient has not achieved at least 5% weight loss from baseline after 12 weeks on the maintenance dose, as they are likely a poor responder 1, 6
• This 12-week checkpoint is critical for determining whether to continue therapy 1, 6

Safety Monitoring

Blood Pressure Surveillance

• Monitor blood pressure before initiating treatment and periodically during therapy, especially in the first 8-12 weeks 1, 5, 6
• Modest but statistically significant increases in systolic and diastolic blood pressure have been observed, most prominently in the first 8 weeks 1, 6
• Uncontrolled hypertension is a contraindication to use 1, 5

Neuropsychiatric Monitoring

• Monitor closely for anxiety, depression, suicidal ideation, and mood changes, particularly in patients under 24 years old 1, 5, 6
• Studies showed no significant difference in depression rates (0.1%-1.3% vs 0.2%-1.6% placebo) or anxiety rates (0.6%-5.4% vs 0.2%-4.3% placebo) 1, 6
• Bupropion carries a black box warning for increased risk of suicidal thoughts in patients younger than 24 years 5

Common Adverse Effects

• Nausea is the most common adverse event and the primary reason for discontinuation 1, 4
• 25% of patients discontinued due to adverse effects versus 10% on placebo (RR 2.39) 1
• Other common reasons for discontinuation include vomiting (0.7%-2%), headache (0.9%-1.8%), dizziness (0.7%-1.4%), and depression (0.2%-0.6%) 1

Cardiovascular Safety

• Available evidence does not indicate an increased risk of major adverse cardiovascular events (MACE) with naltrexone-bupropion ER compared to placebo or active comparators 7
• The difference in MACE proportions between treated and control patients did not exceed 2.5% across studies 7