What are the considerations for using low-dose naltrexone (LDN) in combination with bupropion for weight loss in an adult patient with a history of fibromyalgia or complex regional pain syndrome?

Naltrexone-Bupropion Combination for Weight Loss in Fibromyalgia/CRPS

The naltrexone-bupropion ER combination (Contrave) is FDA-approved for weight management and can be used in patients with fibromyalgia or complex regional pain syndrome, though evidence suggests low-dose naltrexone (LDN) alone provides minimal pain benefit and the combination should be primarily considered for its weight loss effects rather than pain management. 1

Critical Distinction: LDN vs. Naltrexone-Bupropion Dosing

The doses differ dramatically and serve different purposes:

• Low-dose naltrexone (LDN) for pain uses 3.88-5.40 mg daily (typically 4.5 mg), which modulates neuroinflammation and glial cell activity 2, 3
• Naltrexone-bupropion ER for weight loss uses 32 mg naltrexone/360 mg bupropion daily at maintenance dose—approximately 7-fold higher naltrexone dose 4, 1

You cannot achieve therapeutic LDN dosing for pain management while using the FDA-approved naltrexone-bupropion combination product for weight loss. 1

Evidence for LDN in Fibromyalgia/CRPS

The pain management benefits are modest at best:

• LDN showed only a -0.83 average reduction in pain scores in a Veterans Affairs study, with effects described as "small" 5
• One randomized trial found LDN reduced VAS pain scores, but significant placebo effects were observed, and the authors concluded "further studies should be performed to analyze the possible association" 6
• The optimal dose for fibromyalgia appears to be 3.88 mg (ED50) to 5.40 mg (ED95), not the 32 mg contained in naltrexone-bupropion 2
• LDN is generally well-tolerated, with 32% reporting adverse effects including vivid dreams, drowsiness, dizziness, and nausea 5

Naltrexone-Bupropion for Weight Management: Dosing Protocol

Follow this exact titration schedule: 1

• Week 1: 1 tablet (8 mg/90 mg) once daily in the morning
• Week 2: 1 tablet twice daily (morning and afternoon)
• Week 3: 2 tablets in the morning, 1 tablet in the afternoon
• Week 4 onward: 2 tablets twice daily (maintenance dose = 32 mg naltrexone/360 mg bupropion daily)

The second dose must be taken before 3 PM to minimize insomnia risk. 4, 1

Mandatory Safety Screening Before Initiation

Absolute Contraindications

• Seizure disorders or conditions increasing seizure risk (eating disorders, abrupt alcohol/benzodiazepine discontinuation, brain tumor, stroke, head trauma) 4, 1
• Current opioid use—naltrexone blocks opioid receptors and will precipitate withdrawal 1
• MAOI use or within 14 days of discontinuation 4, 1
• Uncontrolled hypertension—bupropion elevates blood pressure 4, 1
• Pregnancy or inadequate contraception 4
• End-stage renal disease 1
• Severe hepatic cirrhosis 4

Pre-Treatment Requirements

• Confirm patient is not taking opioids and has no upcoming procedures requiring opioid analgesia 1
• Baseline blood pressure and heart rate measurement 1
• Mental status examination focusing on suicidal ideation, especially in patients under 24 years old 4
• Pregnancy test and contraception counseling for women of childbearing potential 4

Dose Adjustments for Organ Dysfunction

• Moderate to severe renal impairment (GFR <90 mL/min): Reduce total daily dose by 50% (maximum 1 tablet twice daily) 4, 1
• Moderate to severe hepatic impairment: Do not exceed 1 tablet daily 4, 1

Monitoring Schedule

During Titration and First 8 Weeks

• Weekly to biweekly blood pressure and heart rate checks—modest but statistically significant increases occur 1
• Assess neuropsychiatric symptoms at each visit: anxiety, depression, suicidal ideation, mood changes 1
• Monitor gastrointestinal tolerability (nausea is common) 1

At 12 Weeks: Critical Decision Point

If the patient has not lost at least 5% of baseline body weight at 12 weeks on maintenance dose, discontinue naltrexone-bupropion—they are a poor responder and unlikely to benefit. 1

Ongoing Monitoring

• Periodic blood pressure and heart rate monitoring 1
• Continued psychiatric symptom surveillance 1

Clinical Considerations for Fibromyalgia/CRPS Patients

Pain Management Expectations

• Do not expect significant pain relief from naltrexone-bupropion at weight loss dosing 5, 2
• The 32 mg naltrexone dose is 6-7 times higher than the LDN dose studied for pain (4.5 mg) and operates through different mechanisms 2, 3
• If pain management is the primary goal, consider LDN 4.5 mg daily as a separate intervention, not naltrexone-bupropion 2

Potential Benefits Beyond Weight Loss

• Bupropion may help if the patient has comorbid depression, low energy, or apathy 4
• Bupropion has lower rates of sexual dysfunction compared to SSRIs 4
• The combination addresses weight concerns without the weight gain seen with many other psychiatric medications 4

Common Pitfalls to Avoid

• Do not use naltrexone-bupropion expecting LDN-level pain benefits—the dosing is completely different 2
• Do not forget to discontinue before procedures requiring opioid analgesia (e.g., endoscopies with fentanyl) 1
• Do not take the second dose late in the day—insomnia is a significant risk 4, 1
• Do not continue beyond 12 weeks without achieving ≥5% weight loss—this predicts non-response 1
• Do not abruptly discontinue alcohol or benzodiazepines while on bupropion—this dramatically increases seizure risk 4

Drug Interactions

• Bupropion inhibits CYP2D6, which could affect other medications metabolized by this pathway 1
• No significant pharmacokinetic interaction exists between bupropion and common antidepressants like escitalopram 1
• Exercise extreme caution when combining with other drugs that lower seizure threshold 4

Bottom Line

Use naltrexone-bupropion ER for weight management in fibromyalgia/CRPS patients when weight loss is the primary goal, not pain control. 1 The evidence for pain relief is weak and inconsistent 6, 5, and the naltrexone dosing in this combination product is far too high to replicate LDN's proposed neuroinflammatory modulation 2, 3. Rigorous blood pressure monitoring, seizure risk assessment, and the 12-week weight loss checkpoint are non-negotiable safety measures. 1