Nikhil Jain1, Khaled Himed2, Jeffrey M Toth3, Karen C Briley4, Frank M Phillips5, Safdar N Khan6. 1. Department of Orthopaedics, The Ohio State University Wexner Medical Center, 376 W 10th Ave, Columbus, OH 43210, USA. 2. The Ohio State University School of Medicine, 376 W 10th Ave, Columbus, OH 43210, USA. 3. Department of Orthopaedics, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, USA. 4. Department of Radiology, Wright Center for Innovation and Biomedical Imaging, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Columbus, OH 43210, USA. 5. Midwest Orthopaedics at Rush, Rush University Medical Center, 1611 W Harrison St, Chicago, IL 60612, USA. 6. Department of Orthopaedics, The Ohio State University Wexner Medical Center, 376 W 10th Ave, Columbus, OH 43210, USA. Electronic address: Safdar.Khan@osumc.edu.
Abstract
BACKGROUND CONTEXT: Opioid use is prevalent in the management of pre- and postoperative pain in patients undergoing spinal fusion. There is evidence that opioids downregulate osteoblasts in vitro, and a previous study found that morphine delays the maturation and remodeling of callus in a rat femur fracture model. However, the effect of opioids on healing of spinal fusion has not been investigated before. Isolating the effect of opioid exposure in humans would be limited by the numerous confounding factors that affect fusion healing. Therefore, we have used a well-established rabbit model to study the process of spinal fusion healing that closely mimics humans. PURPOSE: The objective of this work was to study the effect of systemic opioids on the process of healing of spinal fusion in a rabbit posterolateral spinal fusion model. STUDY DESIGN/ SETTING: This is a preclinical animal study. MATERIALS AND METHODS: Twenty-four adult New Zealand white rabbits were studied in two groups after approval from the Institutional Animal Care and Use Committee (IACUC). The opioid group (n=12) received 4 weeks' preoperative and 6 weeks' postoperative transdermal fentanyl. Serum fentanyl levels were measured just before surgery and 4 weeks postoperatively to ensure adequate levels. The control group (n=12) received only perioperative pain control as necessary. All animals underwent a bilateral L5-L6 posterolateral spinal fusion using iliac crest autograft. Animals were euthanized at the 6-week postoperative time point, and assessment of fusion was done by manual palpation, plain radiographs, microcomputed tomography (microCT), and histology. RESULTS: Twelve animals in the control group and 11 animals in the opioid group were available for analysis at the end of 6 weeks. The fusion scores on manual palpation, radiographs, and microCT were not statistically different. Three-dimensional microCT morphometry found that the fusion mass in the opioid group had a lower bone volume (p=.09), a lower trabecular number (p=.02), and a higher trabecular separation (p=.02) compared with the control group. Histologic analysis found areas of incorporation of autograft and unincorporated graft fragments in both groups. In the control group, there was remodeling of de novo woven bone to lamellar organization with incorporation of osteocytes, formation of mature marrow, and relative paucity of hypertrophied osteoblasts lining new bone. Sections from the opioid group showed formation of de novo woven bone, and hypertrophied osteoblasts were seen lining the new bone. There were no sections showing lamellar organization and development of mature marrow elements in the opioid group. Less dense trabeculae on microCT correlated with histologic findings of relatively immature fusion mass in the opioid group. CONCLUSIONS: Systemic opioids led to an inferior quality fusion mass with delay in maturation and remodeling at 6 weeks in this rabbit spinal fusion model. These preliminary results lay the foundation for further research to investigate underlying cellular mechanisms, the temporal fusion process, and the dose-duration relationship of opioids responsible for our findings.
BACKGROUND CONTEXT: Opioid use is prevalent in the management of pre- and postoperative pain in patients undergoing spinal fusion. There is evidence that opioids downregulate osteoblasts in vitro, and a previous study found that morphine delays the maturation and remodeling of callus in a rat femur fracture model. However, the effect of opioids on healing of spinal fusion has not been investigated before. Isolating the effect of opioid exposure in humans would be limited by the numerous confounding factors that affect fusion healing. Therefore, we have used a well-established rabbit model to study the process of spinal fusion healing that closely mimics humans. PURPOSE: The objective of this work was to study the effect of systemic opioids on the process of healing of spinal fusion in a rabbit posterolateral spinal fusion model. STUDY DESIGN/ SETTING: This is a preclinical animal study. MATERIALS AND METHODS: Twenty-four adult New Zealand white rabbits were studied in two groups after approval from the Institutional Animal Care and Use Committee (IACUC). The opioid group (n=12) received 4 weeks' preoperative and 6 weeks' postoperative transdermal fentanyl. Serum fentanyl levels were measured just before surgery and 4 weeks postoperatively to ensure adequate levels. The control group (n=12) received only perioperative pain control as necessary. All animals underwent a bilateral L5-L6 posterolateral spinal fusion using iliac crest autograft. Animals were euthanized at the 6-week postoperative time point, and assessment of fusion was done by manual palpation, plain radiographs, microcomputed tomography (microCT), and histology. RESULTS: Twelve animals in the control group and 11 animals in the opioid group were available for analysis at the end of 6 weeks. The fusion scores on manual palpation, radiographs, and microCT were not statistically different. Three-dimensional microCT morphometry found that the fusion mass in the opioid group had a lower bone volume (p=.09), a lower trabecular number (p=.02), and a higher trabecular separation (p=.02) compared with the control group. Histologic analysis found areas of incorporation of autograft and unincorporated graft fragments in both groups. In the control group, there was remodeling of de novo woven bone to lamellar organization with incorporation of osteocytes, formation of mature marrow, and relative paucity of hypertrophied osteoblasts lining new bone. Sections from the opioid group showed formation of de novo woven bone, and hypertrophied osteoblasts were seen lining the new bone. There were no sections showing lamellar organization and development of mature marrow elements in the opioid group. Less dense trabeculae on microCT correlated with histologic findings of relatively immature fusion mass in the opioid group. CONCLUSIONS: Systemic opioids led to an inferior quality fusion mass with delay in maturation and remodeling at 6 weeks in this rabbit spinal fusion model. These preliminary results lay the foundation for further research to investigate underlying cellular mechanisms, the temporal fusion process, and the dose-duration relationship of opioids responsible for our findings.
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