What is the first line treatment for hyperalgesia?

First-Line Treatment for Hyperalgesia

The first-line treatment for hyperalgesia depends critically on the underlying mechanism: for opioid-induced hyperalgesia, reduce or rotate opioids and add NMDA antagonists like ketamine; for inflammatory hyperalgesia, use acetaminophen or NSAIDs; for neuropathic hyperalgesia, initiate gabapentinoids (gabapentin/pregabalin) or antidepressants (duloxetine/nortriptyline). 1, 2, 3

Identifying the Type of Hyperalgesia

The treatment approach must be guided by the pathophysiological mechanism:

• Opioid-induced hyperalgesia (OIH): Suspect when pain paradoxically worsens with increasing opioid doses, particularly with diffuse allodynia unrelated to the original pain site 2, 4
• Inflammatory hyperalgesia: Associated with tissue injury, inflammation, or surgical trauma with localized tenderness and swelling 3, 5
• Neuropathic hyperalgesia: Results from nerve injury or dysfunction, often with burning pain, allodynia, and sensory changes in dermatomal or nerve distribution patterns 1, 6

Treatment Algorithm by Hyperalgesia Type

For Opioid-Induced Hyperalgesia

Primary intervention is opioid dose reduction or rotation, not adding more analgesics 2, 4:

• Reduce opioid dosage by 25-50% or taper off completely if clinically feasible 2
• Opioid rotation: Switch to methadone or buprenorphine, which have NMDA antagonist properties 2
• Add NMDA receptor antagonists: Ketamine (subanesthetic doses) or dextromethorphan to reverse central sensitization 2, 4
• Consider NSAIDs as adjunctive therapy to reduce opioid requirements 2

For Inflammatory Hyperalgesia

Acetaminophen is the safest first-line choice, followed by NSAIDs for inflammatory pain 3, 7:

• Acetaminophen 1 gram every 4-6 hours (maximum 4 g/day) as initial therapy, particularly effective when started early and used in multimodal regimens 3, 7
• NSAIDs (ibuprofen 400-800 mg every 6-8 hours) are specifically effective for inflammatory hyperalgesia and demonstrate significant suppression of mechanically-induced hyperalgesia 3, 5
• Loteprednol 0.5% topically (for cutaneous hyperalgesia) four times daily for 2 weeks, then taper to twice daily for 2 weeks, then once daily over 6-12 weeks 3
• Avoid NSAIDs with methotrexate, nephrotoxic chemotherapy (cisplatin), or in patients with significant cardiovascular/renal disease 3

For Neuropathic Hyperalgesia

Gabapentinoids or antidepressants are first-line, with topical agents for localized hyperalgesia 1:

Systemic First-Line Options:

• Gabapentin: Start 100-300 mg at bedtime, titrate to 900-3600 mg/day in 3 divided doses over 2-4 weeks 1, 8
• Pregabalin: Start 150 mg/day in 2-3 divided doses, increase to 300 mg/day after 1-2 weeks (maximum 600 mg/day) - offers faster pain relief due to linear pharmacokinetics 1
• Duloxetine (SNRI): Start 30 mg once daily for 1 week, then increase to 60 mg once daily (maximum 120 mg/day) - fewer side effects than tricyclics, no ECG monitoring required 1
• Nortriptyline (TCA): Start 10-25 mg at bedtime, titrate slowly to 75-150 mg/day over 2-4 weeks - requires ECG screening in patients over 40 years 1

Topical First-Line Options for Localized Hyperalgesia:

• 5% Lidocaine patches: Apply daily to painful area, particularly effective for allodynia with minimal systemic absorption 1
• 8% Capsaicin patches: Single 30-60 minute application can provide relief for up to 12 weeks 1

Critical Treatment Principles

Multimodal Analgesia Strategy

Combining medications from different classes provides superior pain relief while reducing individual drug side effects 3, 1:

• Acetaminophen + NSAID for inflammatory hyperalgesia 3
• Gabapentinoid + antidepressant (duloxetine or nortriptyline) for neuropathic hyperalgesia provides additive benefits 1
• Never combine two drugs from the same class with similar kinetics (e.g., two sustained-release opioids) 3

Adequate Dosing and Trial Duration

Inadequate dosing is the most common cause of treatment failure 1:

• Gabapentin requires at least 900 mg/day, preferably 1800-3600 mg/day for efficacy 1
• Allow minimum 2-4 weeks at therapeutic doses before declaring treatment failure 1
• Titrate slowly in elderly patients to minimize adverse effects 1

When to Escalate Treatment

If first-line monotherapy provides partial response after adequate trial:

• Add another first-line agent from a different class rather than switching 1
• If first-line combinations fail, consider tramadol (50 mg once or twice daily, maximum 400 mg/day) as second-line 1
• Avoid strong opioids for long-term neuropathic hyperalgesia management due to risks of dependence, cognitive impairment, and paradoxical pronociception 1

Common Pitfalls to Avoid

• Premature discontinuation: Stopping treatment before reaching therapeutic doses or adequate trial duration (minimum 2 weeks) 1
• Excessive opioid reliance: Particularly problematic in neuropathic hyperalgesia, which is generally less opioid-responsive and risks worsening OIH 1, 2, 4
• Ignoring contraindications: TCAs require ECG screening in patients over 40 years; NSAIDs contraindicated with methotrexate and nephrotoxic chemotherapy 3, 1
• Overlooking dose adjustments: Gabapentinoids require renal dose adjustment; start all medications at lower doses in elderly patients 1