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Repeated Morphine Prolongs Postoperative Pain in Male Rats

Grace, Peter M. PhD*,†,‡; Galer, Erika L. BA*; Strand, Keith A. BA*; Corrigan, Kaci BA*; Berkelhammer, Debra BA*; Maier, Steven F. PhD*; Watkins, Linda R. PhD*

doi: 10.1213/ANE.0000000000003345
Pain and Analgesic Mechanisms: Original Laboratory Research Report

BACKGROUND: Opioids are effective postoperative analgesics. Disturbingly, we have previously reported that opioids such as morphine can worsen inflammatory pain and peripheral and central neuropathic pain. These deleterious effects are mediated by immune mediators that promote neuronal hyperexcitability in the spinal dorsal horn. Herein, we tested whether perioperative morphine could similarly prolong postoperative pain in male rats.

METHODS: Rats were treated with morphine for 7 days, beginning immediately after laparotomy, while the morphine was tapered in a second group. Expression of genes for inflammatory mediators was quantified in the spinal dorsal horn. In the final experiment, morphine was administered before laparotomy for 7 days.

RESULTS: We found that morphine treatment after laparotomy extended postoperative pain by more than 3 weeks (time × treatment: P < .001; time: P < .001; treatment: P < .05). Extension of postoperative pain was not related to morphine withdrawal, as it was not prevented by dose tapering (time × treatment: P = .8; time: P < .001; treatment: P = .9). Prolonged postsurgical pain was associated with increased expression of inflammatory genes, including those encoding Toll-like receptor 4, NOD like receptor protein 3 (NLRP3), nuclear factor kappa B (NFκB), caspase-1, interleukin-1β, and tumor necrosis factor (P < .05). Finally, we showed that of preoperative morphine, concluding immediately before laparotomy, similarly prolonged postoperative pain (time × treatment: P < .001; time: P < .001; treatment: P < .001). There is a critical window for morphine potentiation of pain, as a 7-day course of morphine that concluded 1 week before laparotomy did not prolong postsurgical pain.

CONCLUSIONS: These studies indicate the morphine can have a deleterious effect on postoperative pain. These studies further suggest that longitudinal studies could be performed to test whether opioids similarly prolong postoperative pain in the clinic.

From the *Department of Psychology and Neuroscience, and The Center for Neuroscience, University of Colorado, Boulder, Colorado

Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia

Department of Critical Care and Respiratory Care Research, University of Texas MD Anderson Cancer Center, Houston, Texas.

Accepted for publication February 9, 2018.

Published ahead of print 9 February 2018.

Funding: This work was supported by National Health and Medical Research Council CJ Martin Fellowship (ID 1054091) and American Australian Association Sir Keith Murdoch Fellowship (P. M. Grace); and NIH Grants DE021966, DA023132 (L. R. Watkins).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Peter M. Grace, PhD, Department of Critical Care and Respiratory Care Research, University of Texas MD Anderson Cancer Center, Houston, TX. Address e-mail to

Copyright © 2018 International Anesthesia Research Society
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