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In Reply

Cleveland Clinic Foundation, Stanford University, Palo Alto, CA

We appreciate Dr Prommer's letter and would like to make several comments in reply.

The type of opioid-induced hyperalgesia (OIH) described in our case report does not involve most of the cellular and subcellular mechanisms described in detail by Dr Prommer. Outlined mechanisms apply to OIH associated with opioid maintenance doses and/or opioid withdrawal (OIH_MW). However, the case presented by us concerned OIH associated with the use of very high and escalating opioid doses (OIH_HD). This type of OIH is not mediated through the opioid receptor system. From a mechanistic and management point of view it is important to differentiate OIH_MW from OIH_HD.¹

Dr Prommer suggests that ketamine is "clearly the best current initial management," for OIH_HD because opioid "dose reduction or detoxification is not practical". We do not share Dr Prommer's view. Available evidence clearly suggests that opioid dose reduction or opioid rotation are effective strategies for abolishing or attenuating OIH_HD.¹ Ketamine may be useful as an adjuvant therapeutic agent because some of the symptoms associated with OIH_HD seem to be mediated through the N-methyl-D-aspartate (NMDA) receptor system.²

Dr Prommer is quite firm about the mechanisms underlying OIH_MW. However, there is still some uncertainty about the major mechanisms that mediate OIH_MW and several receptor systems went unmentioned. For example, dynorphin is upregulated by chronic morphine exposure, which results in the activation of non-NMDA voltage-gated calcium channels.^3,4 Similarly, cholecystokinin is upregulated at the level of the rostral ventromedial medulla and periaqueductal gray, which results in the activation of pain facilitating pathways that descend to spinal cord.^5-9 In addition, neurokinin-1 antagonists, cyclooxygenase inhibitors, and nitric oxide synthase inhibitors have all been shown to attenuate OIH_MW.¹⁰

In summary, we would like to reiterate our opinion that opioid dose reduction or opioid rotation should be the first-line treatment for OIH_HD.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

REFERENCES

1. Angst MS, Clark JD: Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 104:570-587, 2006

2. Sakurada T, Watanabe C, Okuda K, et al: Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors. Brain Res Mol Brain Res 98:111-118, 2002

3. Wollemann M, Benyhe S: Non-opioid actions of opioid peptides. Life Sciences 75:257-270, 2004

4. Tang Q, Lynch R, Porreca F, Lai J: Dynorphin A elicits an increase in intracellular calcium in cultured neurons via a non-opioid, non-NMDA mechanism. J Neurophysiol 83:2610-2615, 2000

5. Xie J, Herman D, Stiller C, et al: Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J Neuroscience 25:409-416, 2005

6. Heinricher M, Neubert M: Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiology 92:1982-1989, 2004

7. Bee L, Dickenson A: Rostral ventromedial medulla control of spinal sensory processing in normal and pathophysiological states. Neuroscience 147:786-793, 2007

8. Tortorici V, Nogueira L, Aponte Y, et al: Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter in rats. Pain 112:113-120, 2004

9. Wiesenfeld-Hallin Z, Alster P, Grass S, et al: Opioid sensitivity in antinociception: role of anti-opioid systems with emphasis on cholecystokinin and NMDA receptors. Prog Pain Res Manage 14:237-252, 1999

10. King T, Ossipov M, Vanderah T, et al: Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals 14:194-205, 2005

Related Correspondence

• Opioid-Induced Pain
  Eric E. Prommer
  JCO 2008 26: 3464-3465 [Full Text]

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