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      High concentrations of local anesthetics and long exposure times (e.g. constant administration pump), compared with a single intra‐articular injection.

       Mepivacaine appears to be the least toxic of the clinically available local anesthetics and consequently the recommended drug for intra‐articular administration in practice.

       Some studies have shown that low pH, epinephrine (adrenaline) and some preservatives (sodium metabisulfite) worsen the chondrotoxic effects of local anesthetic solutions [46].

       Pathogenesis

      The chondrotoxicity produced by local anesthetics is time‐ and concentration‐dependent. In vitro, when equine chondrocytes are exposed to clinical concentrations of bupivacaine (0.5%), lidocaine (2%) or mepivacaine (2%), the worse chondrotoxic effects were observed with bupivacaine and the least with mepivacaine [44]. The chondrotoxic effects of bupivacaine and lidocaine seem to be mainly due to necrosis [44]. Ropivacaine is also notably less toxic than bupivacaine or lidocaine [48] and seems to also be less toxic when compared to mepivacaine [48].

      Intra‐articular administrating of local anesthetics causes an inflammatory response early after their administration, as observed in an equine study where a significant increase in synovial nucleated cell counts peaked 24 hours after intra‐articular injections of lidocaine or mepivacaine [49]. This inflammation can also last for a long time, as demonstrated in a study in rabbits where significant inflammation of the articular cartilage and synovial membrane was observed up to 10 days after a single bupivacaine intra‐articular injection [50], and in a study in rats where a reduction in chondrocyte density (50%) lasted up to 6 months following a single intra‐articular injection of bupivacaine 0.5% [51]. However, the clinical relevance of this inflammatory response following single intra‐articular injections seems to be low as evidenced by the lack of equine clinical reports in the literature.

      The clinical effects of intra‐articular local anesthetics may be modified by multiple factors such as: the presence of intact articular cartilage as opposed to chondrocytes or osteochondral tissue used in vitro; the pre‐existing (pathological) state of the articular cartilage; dilution of the drug by synovial fluid and arthroscopic lavage fluid; local absorption of the drug into joint structures and blood vessels; and ongoing joint reparative processes [52].

      There are no reports of clinical cases of chondrotoxicity in equine medicine associated with the use of intra‐articular local anesthetics. An in vivo study showed that single lidocaine 2% or bupivacaine 0.5% injection in normal equine joints has a limited effect on collagen degradation markers and suggested that their administration in this manner is safe [53]. In humans, an important number of clinical cases of chondrolysis have been reported associated with the use of intra‐articular infusions of local anesthetics via pain pumps [54, 55]. Only a very few cases of chondrolysis have been reported following a single intra‐articular injection of bupivacaine (0.25% with adrenaline) [56].

       Prevention

      Using mepivacaine at low concentrations as a single intra‐articular injection seems not to cause any clinical problem; however, repeated administration or continuous infusion of local anesthetics into joints should be avoided. The intact articular surface is not protective against local anesthetic chondrotoxicity [43].

      An in vitro study using human chondrocytes showed that the addition of magnesium sulphate to four different local anesthetic agents resulted in greater cell viability than when cells were treated with a local anesthetic alone [57]. However, a study using co‐cultures of equine cartilage explants and synoviocytes found no difference in cell viability when they were exposed to a local anesthetic alone or in combination with magnesium sulphate [58]. Magnesium sulphate administered intra‐articularly on its own has analgesic properties, it does not cause chondrotoxicity and attenuates the development of experimental osteoarthritis [59, 60]; therefore, it may be considered as an alternative effective and safe intra‐articular drug.

      Intra‐articular administration of morphine is an effective analgesic [61] with a longer duration of effect than the long acting local anesthetic ropivacaine [62]. Additionally, intra‐articular morphine also possesses anti‐inflammatory effects as demonstrated in research horses with acute synovitis, who showed significantly less joint swelling, lower synovial fluid total protein, lower serum and synovial fluid serum amyloid A concentrations, and lower blood white blood cell count compared with intravenously administered morphine [63]. Moreover, intra‐articular morphine does not produce any chondrotoxic effects in human and equine in vitro chondrocyte viability studies [58, 64]; therefore, it may also be considered as an alternative effective and safe drug to provide intra‐articular analgesia.

      An in vitro study using bovine chondrocytes showed that exposure to hyaluronan before exposure to bupivacaine significantly decreased cell death, suggesting that intra‐articular administration of a mixture of local anesthetic and hyaluronan may protect against chondrotoxicity [65]. However, clinical studies are still needed to prove this.

       Diagnosis

      It seems that the chondrotoxic effects of local anesthetics administered as a single intra‐articular injection are subtle and difficult to detect clinically. Chondrolysis is associated with an increase in pain and progressive loss of joint motion that appear a few months after initial surgery, and which progress rapidly (over 4–6 weeks) as described in the human literature [56, 58].

      It is clinically difficult to differentiate the inflammatory process secondary to the reason for performing an intra‐articular block (e.g. post‐arthroscopy pain management) from that caused by the local anesthetic solution. As stated in previous sections, single administration of local anesthetics does not seem to cause any clinical problem and the beneficial effects probably outweigh the risks. If joint pain seems to worsen rather than improve following intra‐articular administration of a local anesthetic, chondrotoxicity should be in the list of differentials. Chondrolysis leads to the disappearance of the articular cartilage very rapidly with loss of joint space as seen in radiography, which will later lead to severe osteoarthritis.

       Treatment

      There is no specific treatment for chondrotoxicity and the therapy is aimed at controlling the inflammatory response, including non‐steroidal anti‐inflammatory drugs, intra‐articular corticosteroids, intra‐articular hyaluronan and physical therapy. In cases of chondrolysis, arthroscopic debridement and arthroplasty are indicated as described in the human literature [56].

       Expected outcome

      The outcome of extensive chondrolysis in the horse would be catastrophic unless affecting a joint that can undergo arthrodesis, such as the proximal intertarsal joint or distal intertarsal or tarsometatarsal joints.

      Allergic Reactions

       Definition

      Allergic or anaphylactic reactions are mediated by immunoglobulin E (IgE) and may occur following administration of any drug. When severe, termed anaphylaxis, they can lead to shock and death if not recognized and treated promptly.

       Risk factors

       Type of local anaesthetic

       Previous exposure to the drug

       Pathogenesis

      Type 1 hypersensitivity reactions occur due to previous sensitization and formation of IgE antibodies. Re‐exposure to the drug will cause mast cell and basophil degranulation with liberation of histamine, leukotrienes and prostaglandins, leading to an anaphylactic reaction. These reactions normally occur very quickly following administration of the drug, usually within 10 minutes, although delayed reactions can also occur and they may progress slowly or rapidly.

The ester‐type local

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