Evaluating the Affect and Reversibility of Opioid-induced Androgen Deficiency in an Orthopaedic Animal Fracture Model

Opioid pain medications are the basis for analgesia after orthopaedic injuries and procedures. However, opioids have many adverse effects, including opioid-induced androgen deficiency.

We evaluated the occurrence and affect of opioid-induced androgen deficiency on osseous union and its ability to be reversed. Additional focus was placed on its perioperative onset and its duration in an orthopaedic animal model.

A femoral osteotomy was created in 75 Sprague-Dawley rats. Postoperatively, animals were randomized into three treatment groups: control, morphine, and morphine plus testosterone. Testosterone levels were recorded preoperatively and at 48 hours, 4 weeks, and 8 weeks postoperatively. Some animals were euthanized at 4 weeks and others at 8 weeks postoperatively. Histology and micro-CT scans were used to evaluate callus. Three-point bend testing was performed to evaluate callus strength.

Serum testosterone levels in the morphine group showed decreased baseline levels of 2.2 ng/mL, 1.4 ng/mL, and 1.4 ng/mL (p < 0.001), whereas the morphine plus testosterone supplementation group showed increased serum levels at 41.7 ng/mL, 11.8 ng/mL, and 19.8 ng/mL (p < 0.001) compared with control animals (3.3 ng/mL, 5.8 ng/mL, 5.2 ng/mL) at 48 hours, 4 weeks, and 8 weeks, respectively. Compared with control animals, histology and micro-CT showed an impedance of callus maturation in the two experimental groups. Morphine-treated animals showed reduction in callus strength at 8 weeks (30% of the contralateral unfractured femur strength compared with 49% seen in the control animals at 8 weeks; p = 0.048); this finding was not fully reversed by testosterone supplementation (33% of the contralateral femur strength; p = 0.171).

Opioid-induced androgen deficiency occurred in this orthopaedic animal model. Although we previously showed that morphine inhibits callus maturation, the current study did not show a rescue of the morphine-treated animals with testosterone supplementation in either morphologic or mechanical testing. Testosterone suppression associated with opioid administration occurred almost immediately (within 48 hours) and was suppressed continually throughout the 8-week duration of study.

Opioid-induced androgen deficiency occurs during the perioperative orthopaedic period. Although its clinical relevance remains unknown, further evaluation is needed to determine if supplementation is warranted during the perioperative period.