A study published in the May issue of the journal Pain suggests that interleukin-1 (IL-1) blockade may amplify and extend the analgesic effects of morphine, reduce side effects, and solve issues of tolerance1. The findings may hold major clinical implications for the use of opiates in a variety of settings.
Researchers in the laboratory of Raz Yirmiya, PhD, professor of psychology at the Hebrew University of Jerusalem in Israel, found that the administration of a neutral (ie, not hyperalgesic) dose of IL-1β abolished morphine analgesia in mice, whereas acute or chronic blockade of IL-1 signaling using any of several IL-1 antagonists significantly potentiated and prolonged analgesic effects. Furthermore, analgesia was extended in strains of mice with genetic defects in IL-1 signaling.
Calling the results "exciting," Pain editor Allan I. Basbaum, PhD, professor and chair of the anatomy department at the W.M. Keck Foundation Center for Integrative Neuroscience at the University of California, San Francisco, tells CIAOMed that the current work demonstrates that opiates affect signaling circuits, and do not have simple inhibitory actions directed at individual cells. Thus, "modulation of the circuit can influence opiate efficacy."
Previous results have indicated that proinflammatory cytokines play a role in pain facilitation, and that genetic or pharmacologic inhibition of IL-1 signaling reduces pain sensitivity in mice. The current study went on to demonstrate that genetic or pharmacologic impairment of IL-1 signaling also prevents the development of opiate tolerance. "These findings suggest that morphine produces an IL-1-mediated homeostatic response, which serves to limit the duration and extent of morphine analgesia, and which underlies the development of tolerance," the authors conclude.
The patients most likely to be affected by the finding are those in "the group that presently is dependent on opiates, namely the cancer population," says Dr. Basbaum. "The big question is whether the number and types of patients who can be controlled long-term on opiates can increase if we can better control side effects and possibly long-term hyperalgesia and tolerance."
Long-term opiate use is often associated with the development of hyperalgesia, which is thought to be one of the mechanisms contributing to morphine tolerance. Previous work has demonstrated that morphine injection results in an increase in proinflammatory cytokine production, which in turn would be expected to increase nociception and promote opiate tolerance.2 The authors point out that modulation of this circuit may be particularly applicable in the treatment of pain associated with inflammatory diseases, in which the chronic production of proinflammatory cytokines renders opioid analgesics ineffective.
Dr. Basbaum expresses some concern, however, about the translation of the current results to the clinical setting. "It is easy to demonstrate opioid tolerance in animals [but] harder in humans for a variety of reasons," he says. "The majority of patients taking opiates are cancer pain patients, where the disease progresses. So, if there is more cancer and more pain, is that what drives the increase in opiate consumption?"
Limitation of morphine dosage may be the most important potential advantage of coadministration with IL-1 inihibitors, according to Dr. Basbaum. "My personal feeling is that [tolerance] does occur and is a problem, but perhaps the biggest problems are the side effects that limit opiate use, and anything that permits a lower dose of opiate to be used would be helpful in that respect."
References:
- Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R. Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain. 2005;115:50-59.
- Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004;24:7353-7365.