Postoperative opioid administration inhibits bone healing in an animal model

Clin Orthop Relat Res. 2013 Dec;471(12):4076-81. doi: 10.1007/s11999-013-3232-z. Epub 2013 Aug 17.


Background: The current mainstay of orthopaedic pain control is opioid analgesics but there are few studies in the literature evaluating the effects of opioids on bone healing.

Questions/purposes: The purpose of this study was to use a rat fracture model to evaluate the effects of opioid administration on osseous union in the acute (4 weeks) and subacute (8 weeks) setting in an operatively stabilized fracture. We asked the following question: does morphine administration alter (1) fracture callus strength; (2) callus volume and formation; and (3) morphology and early remodeling to final osseous union?

Methods: A 0.4-mm femoral osteotomy gap was created in 50 Sprague-Dawley rats using an established model. Postoperatively, rats were randomized to control versus morphine-treated study groups. Equal numbers of rats from each group were euthanized at 4 weeks and 8 weeks postoperatively. Three-point bend biomechanical testing was performed to evaluate postoperative callus strength. Micro-CT scans and histological analyses were used to evaluate postoperative callus volume and formation, morphology, and features of early remodeling.

Results: Biomechanical testing identified a statistically significant (p = 0.048) reduction in callus strength in morphine-treated animals 8 weeks postoperatively compared with controls. Radiographic and histological analysis showed delayed callus maturation and lack of remodeling in the morphine group compared with control animals at 8 weeks. Micro-CT analysis expressed remodeling and resorption as a decrease in callus volume over the two time points. The control group had significant levels of resorption decreasing 29% (p = 0.023) over the 4-week to 8-week time interval. Morphine administration inhibited callus resorption and remodeling with only a 13% decrease (p = 0.393) in callus volume comparing these time points. The callus inhibition associated with morphine administration was not as evident in the acute, 4-week time setting.

Conclusions: Morphine administration inhibited callus strength in this animal model. This finding is likely consistent with the observation that the callus and healing bone appear to have a decreased rate of maturation and remodeling seen at 8 weeks.

Clinical relevance: This study identifies that administration of an opioid pain medication leads to weaker callus and impedes callus maturation compared with controls. These findings may provide the impetus to alter our current orthopaedic analgesic gold standard toward more multimodal and opioid-limiting pain control regimens.

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Analgesics, Opioid / therapeutic use
  • Animals
  • Bony Callus / diagnostic imaging
  • Bony Callus / drug effects*
  • Bony Callus / surgery
  • Femoral Fractures / diagnostic imaging
  • Femoral Fractures / drug therapy
  • Femoral Fractures / surgery*
  • Fracture Healing / drug effects*
  • Male
  • Models, Animal
  • Morphine / pharmacology*
  • Morphine / therapeutic use
  • Osteotomy
  • Pain, Postoperative / diagnostic imaging
  • Pain, Postoperative / drug therapy*
  • Postoperative Period
  • Radiography
  • Rats
  • Rats, Sprague-Dawley


  • Analgesics, Opioid
  • Morphine