title: Evaluating the affect and reversibility of opioid-induced androgen deficiency in an orthopaedic animal fracture model.
abstract: BACKGROUND
  Opioid pain medications are the basis for analgesia after orthopaedic injuries and procedures. However, opioids have many adverse effects, including opioid-induced androgen deficiency.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Orthopaedics, University of Utah, 590 Wakara Way, Salt Lake City, UT, 84108, USA, jesse.chrastil@hsc.utah.edu.
authors.forename: Jesse
authors.initials: J
authors.lastname: Chrastil
authors.forename: Christopher
authors.initials: C
authors.lastname: Sampson
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Higgins
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D005593:Fracture Fixation, Internal / Q000009:adverse effects; D017102:Fracture Healing / Q000187:drug effects*; D020249:Hormone Replacement Therapy; D008297:Male; D009020:Morphine / Q000633:toxicity*; D010027:Osteotomy; D010149:Postoperative Pain / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency*; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: D000701:Analgesics, Opioid; D013739:Testosterone; D009020:Morphine