Postoperative skeletal pain
Authors:   , Steverink Jasper Gerard 
Published: March 2023

This thesis attempts to better understand postoperative skeletal pain, quantify its severity and provide directions for its improved treatment.

Chapter 2 described the current clinical practice in patients undergoing spine surgery regarding postoperative pain and its treatment. Most patients developed moderate opioid-related adverse drug events (ORADEs) while still experiencing pain. To understand the severity of postoperative skeletal pain, an immunohistochemical study quantifying bone sensory innervation was performed on human bone samples from various anatomical locations in Chapter 3. The highest sensory innervation density was found in the periosteum. The anatomical location receiving most sensory innervation was the thoracic spine. Chapter 4 consists of a literature review on bone pain. This chapter identified four pathways involved in generation and maintenance of bone pain. These pathways were the activation, sensitization and sprouting of sensory nerve fibers as well as central sensitization. The high incidence of postoperative ORADEs illustrated the delicate balance between analgesic and side effects of current postoperative pain treatment. Its dense innervation identified the periosteum as a source of pain and potential target for postoperative analgesia.

The second aim was to assess the safety and efficacy of a non-opioid anesthetic (bupivacaine) when applied in high concentrations in musculoskeletal tissues. The toxic effects of bupivacaine in bone, muscle and neural tissue, articular cartilage and the intervertebral disc in vitro were reviewed in Chapter 5. All reported effects in vitro were shown to be reversible in animal and clinical studies, with the exception of chondrotoxicity. The absence of regenerative capacity in vitro likely limits the translation of laboratory findings. Chapter 6 assesses the local toxic effects of high bupivacaine concentrations in a rat model for skeletal surgery. Rats underwent skeletal implantation of a cannula and screw, to allow bolus administration or sustained infusion of bupivacaine in three concentrations at the surgical site. Histological analysis of implant sites after 28 days did not reveal differences between bupivacaine concentrations.

The third aim concerns the development of a clinically relevant hydrogel-based bupivacaine sustained release formulation for use in musculoskeletal surgery. Chapter 7 described the development and in vitro optimization of a ring-shaped hydrogel. The hydrogel displayed tunable mechanical properties and drug-releasing behavior. Drug release was sustained for 72 hours in vitro. The material was implantable, biodegradable and cytocompatible. Chapter 8 revealed that implantation of up to 8 hydrogel rings yielded sustained but low bupivacaine plasma levels, with correspondingly high surgical site levels for 72 hours. Drug release followed a first-order profile. Hydrogels elicited a mild tissue response and degraded in situ. In Chapter 9, a bridging study was performed in sheep according to Good Laboratory Practice (GLP). Sheep received either 8 pedicle screws, 8 pedicle screws combined with unloaded hydrogels, or 8 pedicle screws with bupivacaine-loaded hydrogels. Plasma bupivacaine levels remained tenfold below toxic thresholds, and were sustained for longer compared to subcutaneous infiltration of bupivacaine. Local tissue reaction and screw osseointegration were similar between groups.
Taken together, the results indicate biocompatibility, biodegradability, large systemic safety margins and extended drug release of the bupivacaine-loaded hydrogels in vivo.

The final aim of this thesis was to provide directions for a clinical trial, assessing safety and feasibility of the bupivacaine-loaded hydrogel for use in spine surgery. Chapter 10 presents a protocol for a phase 1B clinical trial, in which female and male adult patients with degenerative spinal disease and scheduled spine surgery are included. The patients will receive 4 or 6 hydrogels, to be co-implanted with pedicle screws. The primary outcome of the study is systemic safety of the bupivacaine hydrogel formulation as defined by the Cmax.