Preliminary study on the effect of parenteral naloxone, alone and in association with calcium gluconate, on bone healing in an ovine "drill hole" model system

Abstract

BackgroundSeveral diseases affect bone healing and physiology. Many drugs that are commonly used in orthopaedics as "analgesics" or anti-inflammatory agents impair bone healing. Stressful conditions are associated with decreased serum osteocalcin concentration. High endorphin levels alter calcium metabolism, blocking the membrane channels by which calcium normally enters cells. The consequent decrease of intracellular calcium impairs the activities of calcium-related enzymes. Naloxone is a pure opioid antagonist. Morphine-induced osteocalcin inhibition was abolished when osteoblasts were incubated with naloxone. Naloxone restored the altered cellular and tissue physiology by removing β-endorphins from specific receptors. However, this is only possible if the circulating Ca concentration is adequate. The aim of the present study was to evaluate the efficacy of parenteral naloxone administration in inducing fast mineralization and callus remodelling in a group of sheep with a standardised bone lesion.MethodsTwenty ewes were randomly assigned to 4 treatment groups. Group A acted as control, group B received a solution of calcium gluconate, group C a solution of naloxone, and group D a solution of calcium gluconate and naloxone. A transverse hole was drilled in the left metacarpus, including both cortices, then parenteral treatment was administered intramuscularly, daily for four weeks. Healing was evaluated by weekly radiographic examination for eight weeks. For quantitative evaluation, the ratio of the radiographic bone density between the drill area and the adjacent cortical bone was calculated. After eight weeks the sheep were slaughtered and a sample of bone was collected for histopathologyResultsGroup D showed a higher radiographic ratio than the other groups. Sheep not treated with naloxone showed a persistently lower ratio in the lateral than the medial cortex (P < 0.01). Histopathology of bone samples showed more caverns and fewer osteoblasts in group D than in the other groups (P ≤ 0.001).ConclusionA low-dose parenteral regimen of naloxone enhances mineralization and remodelling of the callus in healing cortical defects in sheep, especially if associated with calcium gluconate.

Opioid receptor agonists may favorably affect bone mechanical properties in rats with estrogen deficiency-induced osteoporosis

“…The administration of naloxone to OVX rats increased the fracture point load in cancellous bone of the tibial metaphysis; in NOVX rats, there was an increase in the femur mineralization. The improvement of some bone parameters induced by naloxone in rats is consistent with the effect of administration of low-dose naloxone in the sheep: increased mineralization and callus remodeling in a model of bone damage (Petrizzi et al 2007). However, the reports on effects of opioid receptor antagonists on bone resorption are inconsistent; naltrexone caused a decrease of orthodontic tooth movement in rats with experimentally induced cholestasis (Nilforoushan et al 2002), and the topical application of naloxone intensified alveolar bone loss in experimentally induced periodontitis in rats (Queiroz-Junior et al 2013).…”

“…It has been shown that naloxone in small doses has an analgesic effect in humans and animals (Petrizzi et al 2007). Due to the enormous complexity of the endogenous opioid peptide system, and opioid receptors, it is possible that the use of naloxone at a particular dosage may differentially modify the action of individual peptides.…”

Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracture pain

“…While there are relatively few studies that have examined the effect of sustained administration of opioid agonists or antagonists on bone injury/repair/healing, the few publications that have addressed this issue are conflicting. Some studies suggest that opiate agonists are associated with accelerated bone and tissue healing while others suggest the opposite (Poonawala et al, 2005, King et al, 2007, Petrizzi et al, 2007, Zagon et al, 2007). However, one area where there is significant agreement is that opioids do have a variety of non-skeletal side effects that can indirectly inhibit bone healing (Ensrud et al, 2003).…”

New advances in musculoskeletal pain

“…In studies that have examined the effects that opiate agonists and antagonists have on malignant bone remodeling and soft tissue repair the results are controversial. Thus, whereas some studies suggest that opiate agonists stimulate bone and tissue healing (Poonawala et al, 2005) and opiate antagonists accelerate bone and tissue healing (Petrizzi et al, 2007; Zagon et al, 2007) other studies suggest the opposite (King et al, 2007). However, one area where there is nearly complete agreement is that opioids have a variety of CNS side effects that can indirectly inhibit bone healing.…”