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Opioid-Induced Pain

Department of Internal Medicine/Palliative Care, Mayo Clinic Arizona, Scottsdale, AZ

To the Editor:

In response to the article Davis et al,¹ I would like to comment on the mechanisms of opioid-induced pain, the significance of methadone as its potential cause, and potential management options. As demonstrated by their case report, most palliative care specialists find opioid-induced pain to be a phenomenon of high-dose opioid therapy. Paradoxic pain is defined as pain that does not respond to opioids and is worsened by opioid administration in the absence of definite cancer progression.²

Increasingly, evidence suggests that the development of opioid-induced pain sensitivity is mediated by neural mechanisms similar to those that generate neuropathic pain. These neural mechanisms involve N-methyl-D-aspartate (NMDA) receptor activation, which leads to chronic afferent nerve activity, which then results in a central hyperactive state. Mediators of this central sensitization are excitatory amino acids (EAAs) such as glutamate, which are ligands for NMDA receptors. Activation of NMDA receptors generates second-messenger systems that lead not only to persistence of the hyperactive state but also to pathologic changes (eg, formation of dark neurons in the spinal cord), resulting in a permanent imbalance between excitatory and inhibitory neurons with resulting aberrant nerve activity.³

Aberrant nerve activity manifests as persistent hyperalgesia, allodynia, spontaneous pain, and expansion of painful fields as illustrated in the case. At the molecular level, activation of NMDA receptors initiates intracellular processes that cause enduring increases in neuronal excitability.⁴ EAA ligands such as glutamate bind to NMDA and initiate the opening of gated calcium channels, which leads to the hydrolysis of phospholipids mediated by guanosine triphosphate–binding proteins. Products such as and inositol 1,4,5-triphosphate increase the concentration of calcium.⁵ Diacylglycerol mediates activation of an important intracellular messenger called protein kinase C (PKC),⁶ which produces nitrous oxide that diffuses presynaptically to release more EAA.⁷ This EAA influx further activates NMDA receptors, creating a positive feedback loop. Activated PKC also binds to neuronal membranes, and this binding correlates with both hyperalgesia and opioid tolerance. Blocking the effects of PKC reverses morphine tolerance.⁸

Experimentally⁹ and as reported by Davis et al, NMDA antagonists such as ketamine prevent or reduce opioid-induced hyperalgesia. The critical question concerns how exogenous opioid administration activates NMDA receptors, and thus, might be involved in the production of pain.

Experimental evidence suggests that opioids potentiate the inward membrane current (depolarization) induced by EAA such as glutamate.¹⁰ Opioid receptor binding (eg, by morphine) also initiates second-messenger G-protein–mediated PKC translocation and activation.¹¹ This opioid-mediated PKC activation removes magnesium blockade of NMDA receptors, which in effect "activates" the receptors. The resulting activation of NMDA receptors stimulates additional PKC translocation and activation, giving rise, yet again, to a positive feedback loop that can result in hyperalgesia and opioid tolerance. Clearly, the best initial management currently available for opioid-induced pain is NMDA receptor antagonists, because dose reduction or detoxification is not practical for patients experiencing severe pain.

Davis et al reported that methadone produced a brief response. Escalating methadone doses worsened pain. Their case therefore illustrates the limitations of treatment with methadone, which is both a µ agonist and an NMDA receptor antagonist.¹² These findings suggest that high-enough doses of methadone produce a µ effect (ie, an opioid effect) that can overpower the drug's NMDA effect and result in increased pain.¹²

Ketamine, which is as potent an NMDA blocker as methadone, decreased opioid requirements. Ketamine may not be an ideal agent itself beaucase it also has the ability to stimulate µ opioid receptors.¹³ The best approach may be to not rely on pure µ agonists such as fentanyl, which has been associated with opioid-induced pain and has no direct NMDA-blocking activity.¹⁴

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Davis MP, Shaiova LA, Angst MS: When opioids cause pain. J Clin Oncol 25:4497-4498, 2007[Free Full Text]

2. Simonnet G, Rivat C: Opioid-induced hyperalgesia: Abnormal or normal pain? Neuroreport 14:1-7, 2003[CrossRef][Medline]

3. Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 62:259-274, 1995[CrossRef][Medline]

4. Mayer ML, Miller RJ: Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons. Trends Pharmacol Sci 11:254-260, 1990[CrossRef][Medline]

5. Schoepp DD, Conn PJ: Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci 14:13-20, 1993[Medline]

6. Haley JE, Dickenson AH, Schachter M: Electrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat. Neuropharmacology 31:251-258, 1992[CrossRef][Medline]

7. Meller ST, Pechman PS, Gebhart GF, et al: Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 50:7-10, 1992[CrossRef][Medline]

8. Mao J, Mayer DJ, Hayes RL, et al: Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy. J Neurophysiol 70:470-481, 1993[Abstract/Free Full Text]

9. Mao J: NMDA and opioid receptors: Their interactions in antinociception, tolerance and neuroplasticity. Brain Res Brain Res Rev 30:289-304, 1999[CrossRef][Medline]

10. Chen L, Huang LY: Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron 7:319-326, 1991[CrossRef][Medline]

11. Chen L, Huang LY: Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 356:521-523, 1992[CrossRef][Medline]

12. Mao J: Opioid tolerance and neuroplasticity. Novartis Found Symp 261:181-186, 2004; discussion 187-193[CrossRef][Medline]

13. Prommer E: Ketamine to control pain. J Palliat Med 6:443-446, 2003[CrossRef][Medline]

14. Okon TR, George ML: Fentanyl-induced neurotoxicity and paradoxic pain. J Pain Symptom Manage 35:327-333, 2008[CrossRef][Medline]

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