Pharmacokinetics, safety and efficacy of intra‐articular non‐steroidal anti‐inflammatory drug injections for the treatment of osteoarthritis: A narrative review

Abstract

What is known and Objective Osteoarthritis (OA) is a common cause of joint disease and activity limitation in adults. Common therapies to treat OA‐related pain are oral and topical non‐steroidal anti‐inflammatory drugs (NSAIDs) and intra‐articular (IA) corticosteroids. However, prolonged courses of oral NSAIDs are associated with systemic adverse effects and repeat IA corticosteroid injections may cause cartilage degeneration. IA NSAIDs may be an alternative therapy possibly minimizing systemic side effects while maintaining efficacy. Therefore, we sought to summarize the pharmacokinetics, safety and efficacy of IA NSAIDs to help providers make a more informed decision on the use of IA NSAIDs. Methods We searched the National Library of Medicine Database with terms “intraarticular and nsaid”, yielding 1032 results. Only traditional formulations of NSAIDs were considered for inclusion. Animal studies were included if animals were healthy or if the method of arthritis induction was a reasonable model of osteoarthritis. Human studies were included if humans were healthy or if the primary disease studied was osteoarthritis of a large joint. Of 1032 results, 31 research articles met the inclusion criteria and were summarized in this review. Results and Discussion We found that single doses of IA NSAIDs provided far less total systemic and synovial exposure compared to a one week course of oral NSAIDs, but maximum concentrations to the synovium with IA administration were much higher. IA NSAIDs had an excellent safety profile in small animals, large animals and humans, although these injections were associated with non‐specific cartilage inflammation in healthy animals. In animal models, IA NSAIDs had similar efficacy to PO NSAIDs in treating OA‐related pain. In humans, IA NSAIDs had similar efficacy to PO NSAIDS and IA corticosteroids in treating OA‐related pain; however, many trials did not have a placebo control and outcome measures were heterogeneous. What is new and Conclusion Overall, single doses of IA NSAIDs appear safe and efficacious across animals and humans. The optimal use of IA NSAIDs is still to be determined and further research is needed. However IA NSAIDs may be an additional beneficial therapy to treat OA‐related pain. Potential uses may be to augment IA corticosteroids injections, to interrupt multiple IA corticosteroid injections or as an alternative in patients that are high risk for corticosteroid‐related adverse events.

Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

“…When EVs are administered systemically, the half-life is estimated at less than 6 h and they accumulate in the liver and spleen [ 61 ]. In this study, we injected both MSCs and MSC-EVs intra-articular, this is hypothesised to increase bioavailability while reducing systemic exposure, compared to systemic administration [ 62 , 63 ], however very limited data is available on the differences in pharmacokinetics between MSCs and MSC-EVs when injected intra-articular. Systemically EVs are known to have a high degradation rate and clearance [ 61 , 64 , 65 ], to account for this we injected MSC-EVs five times, with 5 day intervals, however that did not result in significant therapeutic efficacy.…”

Pain Management Strategies in Osteoarthritis

“…NSAIDs represent a large class of compounds classified according to their chemical structure, target selectivity, and pharmacokinetic characteristics. NSAIDs include salicylic acid derivatives such as aspirin, aryl acetic acid derivatives such as ibuprofen and naproxen, indole acetic acid derivatives such as indomethacin, anthranilic acid derivatives such as diclofenac, and enolic acid derivatives such as meloxicam [74]. NSAIDs prevent the conversion of arachidonic acid into prostanoids, including prostaglandin, prostacyclin, and thromboxane, by inhibiting the cyclooxygenase pathway.…”

“…Frequently employed NSAIDs such as diclofenac, naproxen, ibuprofen, and aspirin non-selectively restrain both COX-1 and COX-2. In contrast, celecoxib and meloxicam are able to inhibit both COX enzymes, with preferential selectivity for COX-2 [73,74]. COX-2 inhibitors reduce prostacyclin formation in favor of thromboxane, a prothrombotic eicosanoid.…”

“…While the oral administration of NSAIDs is the most common route, intra-articular injections of NSAIDs have gained popularity in various settings, with the aim of potentially increasing NSAID concentration in the target tissue and, simultaneously, reducing the systemic complications associated with the use of NSAIDs [58,72]. Selig DJ and colleagues [74] reviewed the pharmacokinetics, safety, and efficacy of intra-articular NSAID injections, analyzing both animal and human studies reporting on the safety and effectiveness of single doses of intra-articular NSAIDs. The analysis of different studies indicates that single doses of intra-articular NSAIDs result in significantly lower whole systemic and synovial exposure in relation to a one-week administration of oral NSAIDs.…”

Improved Cartilage Protection with Low Molecular Weight Hyaluronic Acid Hydrogel

“…To combat joint inflammation and degeneration, physicians have used a variety of bioactive factors (e.g., NSAIDS and hyaluronic acid [HA]) and biologics (platelet-rich-plasma [PRP] and mesenchymal stromal cells [MSCs]) [ 19 ]. However, their residence time within the synovial fluid may only be days [ 20 , 21 , 22 ], and in a catabolic state, hours. For this reason, researchers have developed therapies that more effectively penetrate and impact tissue properties.…”