Opioid-induced hyperalgesia method is a clinically relevant issue

The manuscript by Mercadante et al. (1) on opioid-induced hyperalgesia after rapid titration with intravenous morphine: switching and re-titration to intravenous methadone is not only interesting, but also provides clinically relevant information. As evidenced by multiple publications, opioid-induced hyperalgesia is no longer an extraneous research phenomenon. Its clinical relevance and importance are increasingly recognized (2,3). While it has proven to be a problem in chronic non-cancer long-term opioid therapy, now it is increasingly clear that opioid hyperalgesia does not spare those suffering with acute pain or cancer pain. Further, the literature shows that it can happen soon after opioid therapy initiation. Opioid hyperalgesia should not be confused with opioid tolerance, allodynia, and withdrawal-associated hyperalgesia, rather it is a distinct phenomenon in all types of pain with all types of opioids at all durations.

Mercadante et al. (1) provide us with illustrations of opioid-induced hyperalgesia with morphine in acute settings, in a surprisingly high proportion of patients (i.e., 12 of 81). They also provide evidence that switching and re-titration through intravenous methadone is a feasible method -- even though methadone has been associated with adverse consequences (including deaths)and is not available in an intravenous form in many countries (4,5).

Preclinical research has illustrated that chronic administration of opioids caused hyperalgesic response (6). While the evidence is overwhelming in reference to opioid-induced hyperalgesia in rats and other animals, the research in humans is still ongoing. Even then, the mechanism of opioid-induced hyperalgesia in acute settings, or, for that matter, chronic settings, is still puzzling with emergence of multiple hypotheses. The emerging literature might appear to be complicating an already confusing picture. To date, we still do not understand why some individuals suffer from opioid-induced hyperalgesia while others do not, even when larger chronic doses of opioids are used. However, this becomes most puzzling when we consider acute pain and the acute administration of opioids. As the authors describe, this is a state of a paradoxical response whereby a patient who is receiving opioids for the treatment of pain might actually become more sensitive to certain painful stimuli. The pain experienced might be the same or even different pain from the original underlying painful condition (7). Even though the precise molecular mechanism is not yet understood, it is generally believed to occur due to neuroplasty changes in the peripheral and central nervous systems leading to sensitization of pronociceptive pathways. But, these mechanisms do not explain because the conditions described here are related to acute pain without disease progression and long-term high dose opioid therapy.

Thus, a clear understanding of the important mechanistic underpinnings and clinical ramifications of opioid hyperalgesia continue to elude the medical community, with significant implications for diagnosis and management.

Mercadante et al. (1) attempt to explain the practical issues involved in managing this unusual and difficult phenomenon. While the study results are preliminary, continued research will be helpful and also helps to lay the foundation for large-scale randomized, double-blind placebo controlled trials.

Footnote

No potential conflict of interest.

References

1. Mercadante S, Ferrera P, Arcuri E, et al. Opioid-induced hyperalgesia after rapid titration with intravenous morphine: switching and re-titration to intravenous methadone. Ann Palliat Med 2012;1:10-3.
2. Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Curr Pain Headache Rep 2011;15:129-36.
3. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011;14:145-61.
4. Centers for Disease Control and Prevention (CDC). CDC grand rounds: prescription drug overdoses - a U.S. epidemic. MMWR Morb Mortal Wkly Rep 2012;61:10-3.
5. Manchikanti L, Fellows B, Ailinani H, et al. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician 2010;13:401-35.
6. Kayan S, Woods LA, Mitchell CL. Morphine-induced hyperalgesia in rats tested on the hot plate. J Pharmacol Exp Ther 1971;177:509-13.
7. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain 2008;24:479-96.