Are opioids effective for treating neuropathic pain?

Opioids for Neuropathic Pain: Evidence-Based Recommendation

Opioids should NOT be used as first-line therapy for neuropathic pain due to limited efficacy, significant risks of addiction, respiratory depression, and potential pronociception—reserve them only as second- or third-line options for patients with moderate to severe pain who have failed first-line treatments. 1, 2

Why Opioids Are Not First-Line

The evidence consistently demonstrates that neuropathic pain is fundamentally resistant to opioid analgesia compared to nociceptive pain 1, 3. This resistance occurs because:

• Neuropathic pain responds poorly to opioids compared to other pain types, with significantly lower efficacy than gabapentinoids, SNRIs, or tricyclic antidepressants 1, 4
• Pronociception risk: In HIV-related neuropathy specifically, opioids may paradoxically worsen pain through upregulation of chemokine receptors (CXCR4) 1
• High side effect burden: 50% of patients experience adverse events, with 25% discontinuing due to intolerable side effects including cognitive impairment, constipation, endocrine dysfunction, and immunosuppression 1
• Addiction and misuse potential: The risks of dependence and diversion significantly outweigh benefits for chronic neuropathic pain management 1

First-Line Treatments You Should Use Instead

Start with these proven effective options 2:

For diffuse neuropathic pain:

• Gabapentin: 100-300 mg at bedtime, titrate to 900-3600 mg/day in 2-3 divided doses (NNT 4.39 for postherpetic neuralgia) 1, 2
• Pregabalin: 150 mg/day in 2-3 divided doses, increase to 300-600 mg/day (faster onset than gabapentin, NNT 4.93) 1, 2, 5
• Duloxetine (SNRI): 60 mg once daily, can increase to 120 mg/day (NNT 5.2 for diabetic neuropathy) 2, 6
• Tricyclic antidepressants: Nortriptyline or desipramine 10-25 mg at bedtime, titrate to 75-150 mg/day (NNT 2.64, but requires ECG screening in patients >40 years) 1, 2

For localized neuropathic pain:

• Lidocaine 5% patches: Apply daily to painful area, minimal systemic absorption (NNT 2.0) 1, 2
• Capsaicin 8% patch: Single 30-60 minute application provides relief for up to 12 weeks (31% achieve >30% pain reduction) 2, 7

When Opioids May Be Considered (Second/Third-Line Only)

Only consider opioids after documented failure of:

1. At least two first-line agents from different classes 1, 2
2. Combination therapy (e.g., gabapentin + duloxetine) 1
3. Adequate trial duration (minimum 2-4 weeks at therapeutic doses) 2

If opioids are necessary 1:

• Tramadol first: 50 mg once or twice daily, maximum 400 mg/day (dual mechanism: weak μ-opioid agonist + SNRI effects, lower abuse potential) 1, 2
• Strong opioids only if tramadol fails: Use lowest effective dose, combine short- and long-acting formulations 1
• Consider morphine + gabapentin combination: Additive effects allow lower doses of each medication 1

Critical Safety Requirements When Prescribing Opioids

Before prescribing any opioid 1:

• Screen for aberrant use risk using SOAPP-R or Opioid Risk Tool 1
• Establish pain treatment agreement 1
• Implement regular monitoring (every 1-3 months) for efficacy, side effects, and signs of misuse 4
• Reassess necessity at each visit—discontinue if ineffective 1

Evidence Quality and Nuances

The evidence supporting opioid use in neuropathic pain is weak 1:

• A 2013 Cochrane review of 14 trials (845 patients) showed 57% of opioid-treated patients achieved ≥33% pain reduction versus 34% with placebo, but studies were limited by small size, short duration (≤12 weeks), and high dropout rates 1
• A 2014 Cochrane review on oxycodone (254 patients) concluded it "cannot be recommended given lack of unbiased evidence" 1
• Systematic reviews show opioids provide modest 14-point reduction on visual analog scale but no improvement in physical or emotional functioning 1

The strongest evidence (NNT 2.67) exists for oxycodone, extended-release morphine, and methadone in postherpetic neuralgia 1, but this still ranks below gabapentinoids and tricyclics in risk-benefit ratio.

Common Pitfalls to Avoid

• Don't prescribe opioids without trying combination first-line therapy first—gabapentin + nortriptyline is more effective than either alone and safer than opioids 1, 2
• Don't use opioids long-term without clear functional improvement—pain reduction alone is insufficient justification 1
• Don't ignore the specific context: Lumbosacral radiculopathy is particularly refractory to all treatments including opioids 2
• Don't forget that tramadol can cause serotonin syndrome when combined with SNRIs/SSRIs 2

Bottom Line Algorithm

1. Start: Gabapentin/pregabalin OR duloxetine/nortriptyline (choose based on comorbidities, age, pain location) 2, 6
2. Partial response: Add second first-line agent from different class 2
3. Inadequate response after 4-6 weeks: Switch to alternative first-line agent 2, 6
4. Still inadequate: Consider tramadol as second-line 1, 2
5. Refractory pain: Time-limited trial of strong opioids with close monitoring, or refer to pain specialist 1, 2

For localized pain at any stage: Add topical lidocaine or capsaicin 8% patch 2, 7