What are the treatment options for hyperalgesia?

Treatment of Hyperalgesia

The treatment approach for hyperalgesia depends critically on its underlying cause: for opioid-induced hyperalgesia, reduce or discontinue opioids and consider NMDA receptor antagonists like ketamine; for neuropathic hyperalgesia, use gabapentinoids (pregabalin or gabapentin) as first-line agents; and for inflammatory hyperalgesia, employ multimodal analgesia with non-opioid agents while avoiding opioid escalation.

Identifying the Type of Hyperalgesia

The first step is determining whether hyperalgesia is opioid-induced, neuropathic, or inflammatory in origin, as this fundamentally changes management 1, 2.

Opioid-Induced Hyperalgesia (OIH)

Suspect OIH when pain escalates despite increasing opioid doses in the absence of disease progression, particularly with diffuse allodynia unassociated with the original pain 1, 2.

• OIH manifests as paradoxical increased pain sensitivity from opioid exposure, where pain may spread beyond the original site or become more diffuse 1, 3
• This phenomenon results from neuroplastic changes in the central nervous system involving NMDA receptors and central glutaminergic pathways 1, 2
• The development of tolerance that necessitates dose escalation facilitates the emergence of hyperalgesia 1

Neuropathic Hyperalgesia

• Characterized by heightened pain sensitivity in the distribution of peripheral or central nerve injury 1
• Often accompanied by allodynia (pain from normally non-painful stimuli) and burning or shooting pain quality 1

Inflammatory Hyperalgesia

• Results from peripheral sensitization of nociceptors after tissue injury 4
• Associated with visible signs of inflammation and localized tenderness 5

Treatment Algorithm for Opioid-Induced Hyperalgesia

Step 1: Opioid Dose Reduction or Discontinuation

The primary intervention for OIH is reducing the opioid dose, tapering off completely, or rotating to a different opioid 1, 2.

• Paradoxically, dose tapering or opioid discontinuation is often associated with amelioration of pain in OIH 1
• Taper slowly over 3-7 days to avoid withdrawal symptoms, as physical dependence resolves within this timeframe 6
• Opioid receptor re-sensitization typically occurs within 3-7 days after discontinuation 6

Step 2: NMDA Receptor Antagonists

Add ketamine as the most evidence-based pharmacological intervention for established OIH 2, 7.

• Ketamine blocks NMDA receptors, which are central to the development of OIH 2, 7
• Case reports demonstrate success with ketamine infusions for acute management 7
• Alternative NMDA antagonists include dextromethorphan and amantadine, though evidence is more limited 7

Step 3: Opioid Rotation

Switch to methadone or buprenorphine, which have unique properties that may reduce hyperalgesia 1, 7.

• Methadone has NMDA receptor antagonist properties in addition to mu-opioid agonism 7
• Buprenorphine demonstrates less pronounced hyperalgesia effects compared to full mu-agonists 1, 6
• However, be aware that methadone itself can cause hyperalgesia with chronic use 1

Step 4: Adjunctive Non-Opioid Analgesics

• Add pregabalin (150-300 mg twice daily), COX-2 inhibitors, or propofol as adjuncts 1, 7
• NSAIDs may help through anti-inflammatory mechanisms 7

Treatment Algorithm for Neuropathic Hyperalgesia

First-Line: Gabapentinoids

Start pregabalin 75 mg twice daily (or 150 mg once daily at bedtime) and titrate to 150-300 mg twice daily based on response 1, 8.

• Pregabalin binds voltage-gated calcium channels to decrease neuropathic pain 1, 8
• FDA-approved for diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and spinal cord injury pain 8
• Patients may experience pain reduction as early as Week 1 8
• Alternative: gabapentin 300 mg three times daily, titrated up to 900-1800 mg daily in divided doses 1
• Common adverse effect is sedation; lower extremity edema may counteract benefits of topical treatments 1

Second-Line: Tricyclic Antidepressants

Use nortriptyline 10-25 mg at bedtime, increasing every 3-7 days to 25-150 mg daily 1.

• Nortriptyline is preferred over amitriptyline due to superior side effect profile 1
• TCAs inhibit presynaptic reuptake of serotonin and norepinephrine while blocking sodium channels 1
• RCTs demonstrate 66% of patients with postherpetic neuralgia achieve significant pain reduction within 3 weeks 1
• Earlier initiation after pain onset improves outcomes 1

Third-Line: Serotonin-Norepinephrine Reuptake Inhibitors

Consider venlafaxine or duloxetine for patients who cannot tolerate gabapentinoids or TCAs 1, 3.

• Venlafaxine showed improvement in symptoms after the first week in a pilot study of 10 primary erythromelalgia patients 1
• Duloxetine 30 mg daily, increased to 60 mg after one week, has a safer profile than TCAs in elderly patients 3

Treatment Algorithm for Inflammatory/Peripheral Hyperalgesia

Multimodal Non-Opioid Approach

Use scheduled acetaminophen 650-1000 mg every 6-8 hours as baseline analgesia, avoiding opioid escalation 3.

• NSAIDs can be effective but carry risks of GI bleeding, acute kidney injury, and cardiovascular events, particularly in seniors 3
• Topical treatments may be beneficial for localized hyperalgesia 1

Topical Interventions for Localized Hyperalgesia

• Compounded topical amitriptyline with ketamine has shown success in case reports 1
• Cryoneurolysis or amniotic membrane application may provide relief in specific contexts like corneal hyperalgesia 1

Special Considerations for Fibromyalgia-Related Hyperalgesia

Pregabalin 300-450 mg daily is FDA-approved and evidence-based for fibromyalgia with hyperalgesia 1, 8.

• 68-78% of patients report improvement on patient global impression of change 8
• The 600 mg daily dose shows no additional benefit over 450 mg but increases adverse effects 8
• Exercise, cognitive behavioral therapy, and patient education are important non-pharmacological adjuncts 1

Critical Pitfalls to Avoid

Do Not Escalate Opioids for OIH

When patients on chronic opioids complain of worsening pain, clinicians face a challenging decision: increasing the opioid dose may paradoxically worsen hyperalgesia 1.

• Look for clues: pain spreading beyond the original site, diffuse allodynia, or pain worsening with dose increases 1, 2
• The cycle of tolerance leading to dose escalation facilitates emergence of hyperalgesia 1

Avoid Combining Opioids with Benzodiazepines or Gabapentinoids in Unmonitored Settings

• This combination compounds CNS depression, fall risk, and respiratory depression, especially in elderly patients 3

Recognize That Maintenance Opioids Do Not Provide Sustained Analgesia

• Methadone and buprenorphine have analgesic duration of 4-8 hours but suppress withdrawal for 24-48 hours 1
• Patients on maintenance therapy demonstrate cross-tolerance to other opioid analgesics and require higher, more frequent doses 1

Monitor for Constipation with Any Opioid Use

• Prescribe scheduled laxatives prophylactically, as constipation is universal with opioids and particularly dangerous in seniors 3