Veterinary Anaesthesia Services International/University of Zurich, Center for Applied Biotechnology and Molecular Medicine, Winterthur, Switzerland
Intra-articular administration (IA) of analgesic drugs is considered useful specifically in diseases that affect a single or only a few joints, such as osteoarthritis. Current pharmacological treatment options are limited. Regarding disease modifying OA drugs (DMOADs), there are more gaps in the arcade of treatment options then options themselves. Systemic applications on the other hand may present with lack of effectiveness in the later stages of OA and with side effects sometimes related to the chronic nature of the disease (OA) and the consequent requirement for long-term administration. A major unmet need in OA treatment consequently is represented by the limited options for intra-articularly administered drugs with long duration of action, since too frequent intra-articular administration presents some problems of itself (for example: need for sedation/anesthesia, risk of infection). Most drugs that are used for IA nowadays, however, have a very short residence time in the joint (for example: plasma and tissue concentrations of meloxicam are not different after IA or IV application in dogs). Careful aseptic conditions need to be applied for all intra-articular drug applications and the maybe altered anatomical layout of a joint with OA needs to be taken into consideration in order to not damage the articular cartilage further by accidental insertion of the needle and possibly ultrasound or radiographic guidance may represent useful techniques to reduce the incidence of such damage. This may become more of a requirement for deeper joints such as the hip or facette joints. Furthermore, aspiration of synovial fluid during the time of needle placement is also a useful technique as it helps a certain correct needle placement, prevents injection of a tissue cylinder (of synovial membrane and other tissues) into the joint, and may diminish the dilution of an injected drug. The latter effect becomes more important when synovial effusion is present and may actually of itself contribute to an improvement of pain. Resting the joint for some time after IA may further increase the residence time of the injectate and enhance (analgesic) effects.
One of the more prevalent benefits of IA is the ease of achieving an effective tissue-site concentration without the need for high plasma concentrations, potentially decreasing the incidence and amount of systemic side effects.
These drugs are the most commonly applied drugs in the perioperative period even though their intra-articular application, particularly in situations of chronic/maladaptive pain is not undisputed. There is a variation in their effectiveness and safety among the different local anesthetics. However, on the basis of issues with chondrocyte toxicity, of limited duration of effect and even plasma concentration, i.e., safety at this point of time, the repeated or continuous administration over time cannot be recommended.
The use of local anesthetics, particularly mepivacaine as a diagnostic tool to assess joint disease (like in horses for lameness diagnosis), however, is recently receiving more attention and dosing schemes have been developed.
Of all opioids, morphine is certainly the most commonly used drug for intraarticular administration, even though some investigations studied other opioids as well. In many studies, morphine has been shown to be overall safe and effective in reducing postoperative pain after intra-articular application. After a single intra-articular application most studies have provided evidence of delayed onset (approx. 3–5 hours) but a prolonged duration of analgesic action (up to 2 days). The long-term use of morphine using other routes of application has been associated with amplification of pain, however, reducing its usefulness in chronic pain situations.
Hyaluronic acid (HA) chemically is a very long glycosaminoglycan structure that in the healthy joint is produced by the type B synoviocytes, the prevalent cell type of the synovial intima. HA and a plasma-ultrafiltate provided by the extracellular matrix together with lubricin form the synovial fluid. HA builds protein links with aggrecans. The HA-aggrecan complex then binds water and type II collagen fibers to build the extracellular matrix of articular cartilage, particularly in diarthrotic synovial joints. In the healthy joint, the high concentration of these complexes are responsible for the viscoelasticity required for joint homeostasis. HA is further involved in anti-inflammatory processes as it inhibits PG E2 synthesis and leukocyte adherence. It also seems to have direct antinociceptive effects. There may be some chondroprotective effects in clinics, but they have been demonstrated so far only in vitro.
HA-preparations show different molecular weights affecting strongly their degree of effect and their residence time. Different dosing regimens are available for human patients only, however most involve cycles of weekly injections (3–4), then an interval of at least 4–6 weeks. More than 6 injections in 6 months should not be performed. Whether or not such dosing schemes may apply to veterinary patients is unclear.
It is currently still debated whether HA has DMOAD-effects with some studies in dogs and rabbits showing are more pronounced tissue repair and other studies pointing more towards HA-treatment rather producing an acceleration of joint damage in OA. Species differences may further complicate the picture.
Other than that, HA in IA seems to be one of the better tolerated treatment options, with a rather low incidence of adverse effects (some may show benign, short lived local reactions).
HA in IA is still today one of the most commonly administered drugs in OA, particularly in the “dry” joint. HA may be and is commonly combined with other drug formulations, such as steroids (and Botox and vanilloid receptor agonists/antagonists).
This group of drugs represents a very commonly applied treatment in IA for OA in human patients. It mainly remains a short lived (1–6 weeks), symptomatic treatment option in cases of severe pain. They are mostly well soluble agents such as betamethasone when in aqueous solution or in the case of triamcinolone or rimexolone which are poorly water soluble, suspensions and emulsions are available. Particularly with the latter ones it is crucial to mix (shake) the vial sufficiently in order to enhance homogeneity of dispersion. Also, there are liposome formulations of dexamethasone are available to produce slow-release formulations. These liposomal formulations should not be mixed with other drugs/solutions.
The non-water soluble formulations have been developed out of a clinical necessity, as water-based solutions have such short residence times that they are sometimes associated with systemic side effects.
Overall, the risk of cartilage defect due to IA corticosteroid seems low, however the sometimes strong pain alleviating effect seems rather short. The use of these drugs in larger joints (elbow, stifle) does not seem to prove better results than systemic NSAIDs and is, therefore, not very common practice in small animals.
In smaller joints, particularly facet joints, there are anecdotal reports of strong, prolonged action when liposomal formulations are used. The application into these joints is being performed under radiographic control. In human patients, the use of corticosteroids is more common when OA-diseased joints present with effusion. The WSAVA Global Pain Council has decided to not list corticosteroids as analgesic drugs in their guidelines.
Platelet-Rich Plasma (PRP)
PRP is a natural concentrate of autologous blood growth factors (TGF-b1, platelet-derived growth factor and other inflammatory modulators) that has been used in a variety of species including humans and dogs to treat degenerative joint disease. For this venous fresh whole blood is collected in an ACD-A anticoagulant solution and centrifuged.
An amount plasma adjacent to the erythrocyte-plasma interface is collected and activated with calcium gluconate. The resulting solution represents the injectate. In dogs a typically used injection volume is 2 mL/joint. The application is currently recommended to be repeated two times at a two-weeks interval.
While this IA-technique is being increasingly applied to clinical cases due to anecdotal reports, scientific evidence of statistical improvement of lameness or pain remains to be clearly shown. Particularly placebo-controlled studies have so far failed to demonstrate clear benefit.
Adipose-tissue derived mesenchymal stem cell (ADMSC) usage is a rapidly expanding medical and veterinary field. It has been demonstrated that AD-MSC can be helpful in the repair of damaged joint structures including cartilage. The idea, in fact, is to recruit endogenous cells to exert trophic functions. Apparently MSC seem to show a tropism for fibrillated articular cartilage when applied IA.
PRP may act as a potentiator for MSC also prolonging the beneficial effects to a period of at least 6 months after a single IA application.
AD-MSC have been applied IA in OA dogs, and significant improvement of peak vertical force and vertical impulse have been demonstrated.
Other studies have demonstrated adequate homing of AD-MSC in partial cartilage defects in dogs and MSC-transformation into chondrocytes with collagen I and II and lubricin expressions
Purified botulinum toxin type A, an extremely potent food-borne toxin has been used in human patients to treat severe joint pain. It is associated with inhibition of various neurotransmitters secreted during peripheral nociceptive stimulation. It may block peripheral and central sensitization. There are suggestions that it may be helpful in treating inflammatory and chronic pain, a combination frequently observed in OA.
In a preliminary study, Botox has been used in IA in elbow and hip joints of 5 dogs with severe OA causing only moderate to significant improvement in 4 of 5 dogs over an 8- to 12-week duration as measured by owner assessment, peak vertical force and vertical impulse. The dose used was 25 units per joint in a single joint application.
The Botox application caused transient slight-moderate side effects, such as mild swelling and redness at the injection site and mild increase in lameness within the first days after application.
The authors of the study concluded that the IA of Botox in OA dogs may not be associated with as profound and prolonged clinical improvements as has been demonstrated previously in humans.
However, further controlled studies are needed and may identify different dose requirements in dogs.