This document discusses opioid induced hyperalgesia (OIH), where increased pain results from opioid use. OIH is caused by changes in the glutaminergic and descending pain pathways in the central nervous system. Patients at risk include those on long-term opioids, perioperative opioid use, and acute opioid administration. OIH presents as diffuse pain not explained by the original condition and increases with higher opioid doses. Management focuses on tapering opioids while adding adjuvant medications targeting NMDA receptors or other pain mechanisms to modulate OIH. A multidisciplinary approach is needed given the complex pathophysiology.

1. Opioid Induced
Hyperalgesia
Ade Wijaya, MD - January 2022

2. Outline
Introduction
Population at Risk
Pathophysiology
Diagnosis – Clinical Presentation
Management
Summary
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3. Introduction
Hyperalgesia (IASP): increased pain from a stimulus that normally
provokes pain
Opioid induced hyperalgesia (OIH) in chronic opioid use, first
described in 1870
3
Merskey H, Bogduk N, Part III: Pain Terms, A Current List with Definitions and Notes on Usage Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy. Seattle: IASP Press; 1994:209–214
Albutt C. On the abuse of hypodermic injections of morphia. Practitioner 1870;5:327–31.

4. Population at Risk
Yi, P., & Pryzbylkowski, P. (2015). Opioid induced hyperalgesia. Pain Medicine, 16(suppl_1), S32-S36. 4
Former opioid addicts who are maintained
on methadone maintenance therapy
Patients who are administered opioids
during the perioperative surgical period
Healthy subjects who are administered
opioids acutely

5. Pathophysiology
Glutaminergic system: excitatory NMDA
Neurotransmitters
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1) NMDA receptors become activated and when inhibited, prevent the
development of tolerance and OIH
2) When the glutamate transporter system is inhibited, there are
increases in the amount of glutamate available to NMDA receptors
3) Cross talk of neural mechanisms of pain and tolerance may exist
4) Prolonged morphine administration induces neurotoxicity via
NMDA receptor mediated apoptotic cell death in the dorsal horn
Silverman S. Opioid induced hyperalgesia: Clinical implications for the pain practitioner. Pain Physician

6. Pathophysiology
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1) Activation of descending pain pathways from the
rostral ventromedial medulla which causes certain
neurons to respond uniquely to opioids
2) Decreased reuptake of neurotransmitters
enhancing certain aspects of the pain pathway
3) Individual genetic factors
Vanderah TW, Suenaga NM, et al. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 2001;21:279–86.
Gardell LR, Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphindependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002;22:6747–55.

7. 7
Roeckel, L. A., Le Coz, G. M., Gavériaux-Ruff, C., & Simonin, F. (2016). Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience, 338, 160-182.

8. Diagnosis – Clinical
Presentation
Pain from OIH is not necessarily located at the source of injury or disease.
Pain manifests as generalized, diffuse, and ill defined; all despite increasing opioid
doses.
Increasing pain is not explained by a progression or worsening of the underlying
condition and should always be ruled out.
Increase in perceived pain with an increase in opioid use
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Low Y, Clarke CF, Huh BK, et al. Opioid-induce hyperalgesia: A review of epidemiology, mechanisms and management. Singapore Med J 2012;53:357–60.
Yi, P., & Pryzbylkowski, P. (2015). Opioid induced hyperalgesia. Pain Medicine, 16(suppl_1), S32-S36.

9. Management
- Weaning off opioids completely
- Opioid rotation
- Adding opioid sparing adjuvant medications such as a NSAID,
acetaminophen, an anticonvulsant or an antidepressant
- NMDA antagonists: ketamine, methadone, dextromethorphan,
buprenorphine
- Other agents such as pregablin, propofol, and Cox-2 inhibitors can
play a role in modulating OIH. Each medication interacts at different
aspects of the pain pathway; pregablin at neuronal tissues, propofol
at the GABA receptors, and COX-2 inhibitors through inhibition of
prostaglandin synthesis
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Yi, P., & Pryzbylkowski, P. (2015). Opioid induced hyperalgesia. Pain Medicine, 16(suppl_1), S32-S36.

10. Summary
More opioids are prescribed  increase OIH
Complex pathophysiology
Needs to be differentiate with opioid tolerance and withdrawal
Multidisciplinary approach
4/5/2022 Opioid Induced Hyperalgesia 10

11. Thank you