What causes opioid-induced hyperalgesia (OIH)?

From the Guidelines

Opioid-induced hyperalgesia is primarily caused by neuroplastic changes in pain perception, resulting from prolonged opioid use, which leads to increased pain sensitivity and decreased analgesic effects of opioids. The mechanisms underlying this condition involve the activation of N-methyl-D-aspartate (NMDA) receptors and opioid receptors, leading to excitatory amino acid release and upregulation of excitatory neurotransmitters like glutamate 1. Additionally, opioids can activate glial cells, triggering inflammatory responses that enhance pain signaling.

Key Mechanisms

• Activation of NMDA receptors in the central nervous system
• Upregulation of excitatory neurotransmitters like glutamate
• Activation of glial cells (microglia and astrocytes) in the spinal cord and brain
• Changes in descending pain modulatory pathways
• Development of anti-opioid systems involving cholecystokinin and dynorphin

Clinical Implications

Opioid-induced hyperalgesia can manifest as increased pain despite escalating opioid doses, often with pain extending beyond the original painful area. Management strategies may include opioid rotation, dose reduction, or adding adjuvant medications such as ketamine, gabapentinoids, or alpha-2 agonists 1. It is essential to distinguish opioid-induced hyperalgesia from tolerance, as they require different management approaches.

Recent Evidence

A more recent study published in 2018 highlights the challenges of managing opioid-induced hyperalgesia, emphasizing the need for careful consideration of dose adjustments and the potential benefits of nonopioid analgesics 1. However, the most recent and highest quality study on this topic is crucial for guiding clinical decisions, and in this case, the 2018 study provides valuable insights into the mechanisms and management of opioid-induced hyperalgesia.

From the FDA Drug Label

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia

The cause of Opioid-Induced Hyperalgesia (OIH) is not fully understood, but it is thought to be related to the use of opioid analgesics. Multiple biochemical pathways have been implicated, and there is a strong biologic plausibility between opioid analgesics and OIH and allodynia 2.

From the Research

Opioid-Induced Hyperalgesia Mechanisms

• Opioid-induced hyperalgesia (OIH) is a state of nociceptive sensitization caused by exposure to opioids, leading to a paradoxical response where patients receiving opioids for pain treatment become more sensitive to certain painful stimuli 3.
• The precise molecular mechanism of OIH is not yet understood but is thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways 3.
• Proposed mechanisms for OIH include:
  • Central glutaminergic system
  • Spinal dynorphins
  • Descending facilitation
  • Genetic mechanisms
  • Decreased reuptake and enhanced nociceptive response
• The central glutaminergic system, particularly N-methyl-D-aspartate (NMDA) receptors, is considered a key mechanism in OIH 3, 4, 5.

Clinical Implications and Diagnosis

• OIH is a recognized complication of opioid therapy, distinct from tolerance, and can lead to loss of opioid efficacy in some patients 3, 4.
• Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain 3.
• Diagnosis and treatment of OIH require differentiation from clinically worsening pain and tolerance, as treatment strategies differ 4, 6.

Treatment Strategies

• Treatment options for OIH include:
  • Reducing the opioid dosage
  • Tapering off opioids
  • Supplementation with NMDA receptor modulators
  • Opioid rotation
  • Use of specific NMDA receptor antagonists
  • Office-based detoxification 3, 4, 6.
• The role of sublingual buprenorphine appears to be an attractive, simple option for the treatment of OIH 4.

Clinical Relevance and Debate

• The clinical relevance of OIH is debated, with some studies suggesting it may not be a clinically significant phenomenon 7.
• Randomized clinical trials are needed to differentiate OIH from tolerance, withdrawal-mediated pain sensitivity, and worsening of the disease 7.
• Current evidence does not support OIH as a sound rationale for deprescribing opioids in patients with chronic pain 7.