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In Reply

Departments of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH

Martin Angst

Department of Anesthesia, Stanford University School of Medicine, Stanford, CA

We thank the authors for sharing their view and experience. It is possible that the incidence of opioid-induced hyperalgesia (OIH) associated with very high doses or with rapid opioid titration is underestimated. The incidence is not known and reports by clinicians observing this type of OIH is certainly encouraged. We would like to point out that our case illustrates OIH observed in the context of very high opioid doses. This type of OIH needs to be distinguished from two other types (1): OIH observed during opioid maintenance therapy, and (2) OIH evoked by ultra-low or sub-clinical doses.

OIH occurring at very high doses is uniquely associated with allodynia and myocloni and is not reversed by opioid receptor antagonists.^1-3 This type of OIH is reported anecdotally and is almost uniformly associated with the use of a phenanthrene opioid, particularly morphine.⁴ Mechanisms that have been implicated are activation of the N-methyl-D-aspartate receptor system by morphine-3-glucuronide and/or antiglycinergic means. This type of OIH is typically attenuated or reversed by opioid dose reduction and/or rotation.

OIH associated with maintenance therapy is not associated with allodynia (pain evoked by normally nonpainful touch), but instead produces hyperalgesia, a general sensitivity to stimuli that are painful per se.^4-8 The mechanism behind this type of OIH is initiated by µ-opioid receptor activation, is multifaceted, and involves several different neurotransmitter systems at the level of the peripheral nerve, the spinal cord, and supraspinal centers.^9-14

It has been speculated that opioids have a bimodal effect at the µ receptor. At very low doses, they may activate Gs proteins and trigger an excitatory rather than inhibitory cascade. The clinical significance of this phenomenon is unclear and there are conflicting results as to the benefits of combining opioids with a low dose of an opioid receptor antagonist to block the excitatory effects.³

While opioid rotation and dose reduction are valuable strategies to attenuate or reverse OIH associated with very high and escalating opioid doses, it seems counterintuitive to recommend switching to morphine. Morphine has been most often implicated in causing this type of OIH. Switching from a phenanthrene (eg, morphine) to a piperidine opioid (eg, fentanyl) has typically been helpful for reducing OIH and is our suggested approach. The use of magnesium or ultra-low doses of naloxone for this type of hyperalgesia has not been investigated and lacks a scientific basis. Magnesium has been proposed for use in OIH observed during opioid maintenance therapy and the use of ultra-low doses of naloxone has been proposed for alleviating hyperalgesia evoked by ultra-low-dose opioids. Both approaches are experimental at best.

While we agree with the authors that decreasing the opioid dose is a reasonable first step if OIH is suspected in the context of very high and escalating doses, the utility of this approach for the other types of OIH remains to be determined.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

REFERENCES

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11. Heinricher MM, McGaraughty S, Tortorici V: Circuitry underlying anti-opioid actions of cholecystokinin within the rostral ventromedial medulla. J Neurophysiol 85:280-286, 2001[Abstract/Free Full Text]

12. Heinricher MM, Neubert MJ: neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophys 92:1982-1989, 2004[Abstract/Free Full Text]

13. Xie JY, Herman DS, Stiller CO, et al: Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J Neurosci 25:409-416, 2005[Abstract/Free Full Text]

14. Vanderah TW, Suenaga NM, Ossipov MH, et al: Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 21:279-286, 2001[Abstract/Free Full Text]

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