Ultralow dose fentanyl prevents development of chronic neuropathic pain in rats

Authors

  • Elzbieta P. Wala, PhD
  • Joseph R. Holtman Jr, MD, PhD
  • Paul A. Sloan, MD

DOI:

https://doi.org/10.5055/jom.2013.0150

Abstract

Background: Opioids may cause progressive enhancement of pain sensitivity (opioid-induced hyperalgesia [OIH]) and thus, exacerbate existing pain. Animal studies also demonstrate paradoxical OIH with an ultralow dose (ULD, subanalgesic) of opioid; eg, the µ-opioid, morphine. Repeated administration of ULD-morphine resulted in tolerance to ULD-OIH. Prior exposure to ULD-morphine prolonged subsequent morphine antinociception in intact rats (delay of tolerance) and blocked neuropathic pain in nerve-injured rats (no hyperalgesia). Hence, pre-emptive desensitization of the excitatory function of opioid receptors may reduce further activation of a pain facilitatory system exerted by opioid or nerve injury. Objective: We determined if ULD-fentanyl (µ-opioid) and U50488H (?-opioid) also affect post-nerve-injury neuropathy (a rat model of chronic constriction nerve injury [CCI]). Design: Fentanyl (0.5-500 ng/kg) was administered acutely in noninjured rats. Chronic fentanyl (5 ng/kg/day) was initiated either immediately after CCI (day 1-28) or when neuropathy was established (day 7-14) in nerve-injured rats. U50488H (25 µg/kg/day) was given on day 1-28 post-CCI. Saline served as control. Responsiveness was assessed using tail-flick and paw-pressure tests, respectively, in intact and CCI Sprague-Dawley rats of both sexes. Results: ULD-fentanyl evoked pain sensitization in noninjured rats. ULD-OIH was related to dose (inversely), gender (female > male), and was reversed by ketamine. Neuropathy developed after CCI in control (saline) rats. This was not observed in rats of either sex exposed to ULD-fentanyl on day 1-28 post-CCI. Rats treated with ULD-fentanyl from day 7 after CCI exhibited hyperalgesia similar to control rats. U50488H did not block post-CCI neuropathy (regardless of gender). Conclusions: Pre-emptive use of ULD µ-opioid (not ?-opiod) blocked initiation (not maintenance) of neuropathic pain after CCI in rats. These data may suggest a novel treatment approach in situations when the potential development of neuropathy can be anticipated. Keywords: neuropathy, opioid-induced hyperalgesia, µ-opioid agonist, ?-opioid agonist, subanalgesic dose, neuropathy initiation, neuropathy maintenance

Author Biographies

Elzbieta P. Wala, PhD

Elzbieta P. Wala, PhD, Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, Kentucky.

Joseph R. Holtman Jr, MD, PhD

Joseph R. Holtman Jr, MD, PhD, Departments of Anesthesiology and Molecular Biology and Therapeutics, Loyola University Medical Center, Maywood, Illinois.

Paul A. Sloan, MD

Paul A. Sloan, MD, Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, Kentucky.

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Published

03/01/2013

How to Cite

Wala, PhD, E. P., J. R. Holtman Jr, MD, PhD, and P. A. Sloan, MD. “Ultralow Dose Fentanyl Prevents Development of Chronic Neuropathic Pain in Rats”. Journal of Opioid Management, vol. 9, no. 2, Mar. 2013, pp. 85-96, doi:10.5055/jom.2013.0150.

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