Comparison of in vitro and in vivo Toxicity of Bupivacaine in Musculoskeletal Applications

Abstract

The recent societal debate on opioid use in treating postoperative pain has sparked the development of long-acting, opioid-free analgesic alternatives, often using the amino-amide local anesthetic bupivacaine as active pharmaceutical ingredient. A potential application is musculoskeletal surgeries, as these interventions rank amongst the most painful overall. Current literature showed that bupivacaine induced dose-dependent myo-, chondro-, and neurotoxicity, as well as delayed osteogenesis and disturbed wound healing in vitro. These observations did not translate to animal and clinical research, where toxic phenomena were seldom reported. An exception was bupivacaine-induced chondrotoxicity, which can mainly occur during continuous joint infusion. To decrease opioid consumption and provide sustained pain relief following musculoskeletal surgery, new strategies incorporating high concentrations of bupivacaine in drug delivery carriers are currently being developed. Local toxicity of these high concentrations is an area of further research. This review appraises relevant in vitro, animal and clinical studies on musculoskeletal local toxicity of bupivacaine.

Lack of concentration‐dependent local toxicity of highly concentrated (5%) versus conventional 0.5% bupivacaine following musculoskeletal surgery in a rat model

“…No significant differences between sustained and dose‐dump administration were observed for any histological parameter. Altogether these findings agree with previous studies on 0.25% and 0.5% bupivacaine, indicating that the reported in vitro toxicity of bupivacaine does not translate to in vivo situations, where regenerative processes can take place [9, 28]. This conclusion now appears to be extendable to higher concentrations of bupivacaine.…”

“…An advantage of local bupivacaine sustained‐release formulations is their relatively high drug concentration at the target site, while systemic levels stay low [8]. However, multiple in vitro studies report concentration‐dependent cytotoxicity of musculoskeletal cell types following bupivacaine exposure [9]. For example, bupivacaine at subclinical concentrations induces concentration‐dependent decreases in mesenchymal stem cell proliferation, osteogenesis and wound healing in vitro, three important processes for successful recovery after musculoskeletal surgery [10].…”

“…For example, bupivacaine at subclinical concentrations induces concentration‐dependent decreases in mesenchymal stem cell proliferation, osteogenesis and wound healing in vitro, three important processes for successful recovery after musculoskeletal surgery [10]. The translatability of bupivacaine in vitro toxicity to the in vivo situation has recently been reviewed [9].…”

Persistent Radiculopathy Subsequent to Selective Nerve Root Block

“…The left foot drop, muscle atrophy, and patella tendon hyporeflexia occurred in a patient with preexisting neuroforamen narrowing. He received a higher-than-normal volume of injectables [5], including contrast agents, bupivacaine, and steroid, which are cytotoxic [6][7][8][9]. For lumbar selective nerve root blocks, 1 mL of medication and anesthetics are usually injected following up to 0.5 mL of contrast [5].…”

Fluoroscopic-guided procedures of the lower extremity

“…Intraarticular injection of local anesthetics, although widely practiced, remains an off-label, non-FDA approved use [ 3 , 5 ]. Some studies have shown dose-dependent (high concentration and long exposure) chondrolysis in vivo especially when there is underlying cartilage abnormality; however, recent in vitro studies have not found this effect to be significant [ 17 , 18 ]. In vivo studies also showed no definite correlation of anesthetic potency with chondrocytotoxicity; ropivacaine was shown to be the least toxic of the agents studied [ 17 ].…”