Opioid-Induced Hyperalgesia (OIH)

Definition

Opioid-Induced Hyperalgesia (OIH) is a state of increased pain sensitivity caused by prolonged opioid exposure, leading to a reduced analgesic effect and heightened perception of pain.

Mechanisms of OIH

1. Central Sensitization

• Chronic opioid exposure leads to neuroplastic changes in the central nervous system.

• Increased NMDA receptor activation contributes to central hyperexcitability.

2. Glutamate and NMDA Receptor Activation

• Opioids increase glutamate release, which activates NMDA receptors, leading to enhanced pain transmission.

3. Descending Facilitation (Spinal Cord Changes)

• Opioids reduce descending inhibitory control and increase descending facilitatory pathways, leading to pain amplification.

4. Increased Pro-Nociceptive Pathways

• Dynorphins and Pro-Nociceptive Peptides are upregulated, enhancing pain perception.

5. Neuroinflammation

• Chronic opioid use triggers glial cell activation, releasing pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), which amplify pain.

Clinical Features of OIH

✅ Paradoxical increase in pain despite escalating opioid doses

✅ Pain becomes diffuse, extending beyond the original painful site

✅ Pain has a burning, allodynic, or hyperalgesic character

✅ Increased pain sensitivity to non-noxious stimuli (allodynia)

✅ Pain worsens with opioid dose escalation and improves with opioid reduction

Diagnosis of Opioid-Induced Hyperalgesia

1. Clinical Criteria

• Pain worsening despite increasing opioid dose

• Pain spreads beyond the primary site of injury

• Reduced effectiveness of opioids over time

2. Differentiation from Opioid Tolerance

Feature	Opioid Tolerance	Opioid-Induced Hyperalgesia (OIH)
Mechanism	Downregulation of opioid receptors	Central sensitization, NMDA activation
Pain Characteristics	Same location, opioid-responsive	Diffuse, opioid-resistant
Response to Opioid Dose Increase	Improves pain	Worsens pain
Management	Increase dose or switch opioids	Reduce or discontinue opioids

Management of Opioid-Induced Hyperalgesia

1. Opioid Dose Reduction or Discontinuation

• Gradual tapering of opioids to reduce hyperalgesia.

• Avoid abrupt discontinuation to prevent withdrawal.

2. NMDA Receptor Antagonists

• Ketamine (0.1–0.5 mg/kg IV infusion) – Blocks NMDA receptor activation.

• Magnesium sulfate (30–50 mg/kg IV) – Modulates NMDA activity.

3. Opioid Rotation (Switching to a Different Opioid)

• Methadone (which has NMDA antagonism) may reduce OIH.

• Buprenorphine (a partial agonist) has less OIH risk.

4. Adjunctive Non-Opioid Analgesics

• Multimodal analgesia with NSAIDs, paracetamol, and gabapentinoids.

• Gabapentin/Pregabalin – Modulates calcium channels to reduce pain.

• Clonidine/Dexmedetomidine – Alpha-2 agonists for pain modulation.

5. Non-Pharmacological Approaches

✅ Cognitive Behavioral Therapy (CBT) – Pain coping strategies.

✅ Physical Therapy – Reduces opioid dependence.

✅ Transcutaneous Electrical Nerve Stimulation (TENS) – Modulates pain perception.

MCQs on Opioid-Induced Hyperalgesia

1. The primary mechanism responsible for opioid-induced hyperalgesia is:

A) Opioid receptor downregulation

B) NMDA receptor activation

C) Increased dopamine release

D) Increased serotonin levels

Answer: B) NMDA receptor activation

2. Which of the following best differentiates opioid tolerance from opioid-induced hyperalgesia?

A) Pain relief with opioid dose escalation

B) Diffuse pain beyond original site

C) Reduction of opioid receptor sensitivity

D) Increased sedation with opioid use

Answer: B) Diffuse pain beyond original site

3. Which drug is most effective in reversing opioid-induced hyperalgesia?

A) Morphine

B) Ketamine

C) Fentanyl

D) Hydromorphone

Answer: B) Ketamine

4. A patient on chronic opioids reports worsening pain despite increasing opioid doses. What is the best management approach?

A) Increase opioid dose further

B) Add benzodiazepines

C) Reduce opioid dose and consider ketamine

D) Switch to another strong opioid

Answer: C) Reduce opioid dose and consider ketamine

5. Which of the following is least likely to contribute to opioid-induced hyperalgesia?

A) NMDA receptor activation

B) Central sensitization

C) Increased descending inhibition

D) Microglial activation

Answer: C) Increased descending inhibition

Summary Table

Aspect	Details
Definition	Increased pain sensitivity due to prolonged opioid use
Mechanisms	NMDA receptor activation, central sensitization, neuroinflammation
Symptoms	Worsening pain despite opioid escalation, pain spreading beyond the initial site
Diagnosis	Clinical assessment, differentiation from tolerance
Management	Opioid reduction, NMDA antagonists (Ketamine), opioid rotation, multimodal analgesia
Non-Pharmacological	CBT, Physical Therapy, TENS

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