Systematic review of rat models with temporomandibular osteoarthritis suitable for the study of emerging prolonged intra-articular drug delivery systems

Abstract Purpose Development of minimally invasive therapies for temporomandibular joint osteoarthritis (TMJOA) has focused on drug intra-articular injections to avoid the systemic adverse effects experienced when these substances are administered orally. Therefore, we performed a systematic review to answer the question “Which method of induction of a TMJOA-related-pain model in rats leads to prolonged painful symptoms, allowing the best assessment of a sustained drug delivery system?” Materials and Methods Following the PRISMA guidelines, we searched MEDLINE for papers published from 1994 to July 2020 on a TMJ arthritis model using rats. We identified the means of pain induction and of nociception assessment. We assessed protocol bias using an adaptation of the QUADAS-2 tool. Animal selection, the reference standard method of pain assessment, applicability of a statistical assessment, and flow and timing were assessed. Results Of the 59 full papers we reviewed, 41 performed no pain assessment after the first 7 days following induction of the TMJ-related pain model. We eventually identified 18 long-term TMJOA-related pain models. Pain was induced by injection of toxic substances, most commonly Freund’s complete adjuvant (50 μg per 50 μl), formalin at various concentrations, or monosodium iodoacetate (50 mg per 50 μl), into the TMJ, or by physical methods. Few studies reported data on pain after 21 days of follow-up. Heterogeneity of induction methods, pain assessment methods, and flow and timing biases precluded a meta-analysis. Conclusion Given that pain is 1 of the main symptoms of TMJOA, experimental study protocols should include long-term pain assessment.