Opioid Induced Hyperalgesia

  • Both animal and human studies have demonstrated that prolonged use of opioids can lead to a state of abnormal pain sensitivity, sometimes called opioid induced hyperalgesia (OIH).
  • The prevalence of OIH in clinical practice is unknown. The published literature examines the phenomena in three groups: 1) patients undergoing surgery who receive high doses of opioids perioperatively 2) patients receiving methadone maintenance for opioid addiction and 3) experimental pain testing on healthy volunteers exposed to acute opioid administration.
  • There are neurobiological similarities between the symptoms of hyperalgesia and allodynia that typify neuropathic pain, opioid induced hyperalgesia and opioid tolerance. Mechanisms for these phenomena relate to neuroplastic changes in the peripheral and central nervous system that lead to sensitisation of pronociceptive pathways.
  • Opioid induced hyperalgesia is not usually seen in the absence of observed tolerance to opioid analgesia.
  • While there are many proposed mechanisms for OIH, five mechanisms are probably the most the important involving:

• the central glutaminergic system particularly the excitatory amino acid N-methyl-D-aspartate
• increase in spinal dynorphins leading to release of excitatory neuropeptides from primary afferents
• activation of neurons in the rostroventral medulla that facilitate spinal nociceptive processing
• genetic mechanisms which influence pain sensitivity, response to analgesia and
• decreased reuptake of neurotransmitters from primary afferent neurons and enhanced nociceptive response in spinal neurons

  • Clinically, hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality.
  • Management of opioid induced hyperalgesia requires opioid dose reduction or changing to an alternative opioid preparation.

Further Reading

  • Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006; 104:570–587.
  • Cohen SP, Christo PJ, Wang S, et al. The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. Regional Anesthesia and Pain Medicine 2008; 33: 199-206.
  • Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent. Drug and Alcohol Dependence 2001; 63: 139-146.
  • Lee M, Silverman S, Hans H, et al A comprehensive review of opioid induced hyperalgesia. Pain Physician 2011; 14: 145-161.
  • Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002; 100: 213–217.
  • Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Current Pain and Headache Reports 2011; 15: 129-36.