Joint pain is among the most frequent chronic pain states [
1]. In most cases, chronic joint pain results from osteoarthritis (OA), which has a prevalence of about 90% in the older population [
2,
3]. At this time OA cannot be cured. Therefore, symptomatic pain relief is essential because pain is one of the most disabling symptoms and can thus cause a significant aggravation of joint dysfunction [
4]. Most often, nonsteroidal anti-inflammatory drugs (NSAIDs) are clinically used. NSAIDs can effectively reduce inflammation and pain, particularly in exacerbated OA [
5], but can also cause significant side effects such as gastrointestinal and renal disorders [
6,
7] when taken regularly. Alternatively, whenever single or few joints are affected, local antinociceptive therapy might be considered. In this respect, hyaluronic acid (HA) preparations are often used. Subject to the preparation used, HA is injected into the joint one, three, or up to six times at weekly intervals [
8,
9]. Some studies reported good analgesic effects of HA preparations [
10‐
13] whereas others found an antinociceptive action in the range of placebo effects [
13,
14]. In fact, clinical trials to prove the efficacy of HA preparations in OA are compromised by the large placebo effect in this patient group [
15]. The injection of a knee is an active and invasive treatment and hence powerful placebo effects may mask true antinociceptive effects of compounds. In addition the tools to record these effects, such as Western Ontario MacMaster Questionnaire, are subjective in nature and hence a source of bias. Furthermore, it is important which patients are included. For example, one study included patients with poly-articular OA and knee effusions. For the overall population there was no significant analgesic effect but when these patients were removed from the analysis, the stabilised HA was shown to be highly efficacious over saline in patients with knee OA [
13]. Comprehensive meta-analyses stressed the poor quality of many trials [
16], the heterogeneity among the studies [
17], and came to different conclusions, ranging from no effect [
16], or a small effect, with highest-molecular-weight HA possibly being more efficacious than lower-molecular weight HA in treating knee OA [
17]. The review from Bellamy et al. [
18] concludes "overall, the analyses support the use of the HA class of products in the treatment of knee OA". In addition the injection of different HA preparations at different doses is usually not feasible.
In this respect, preclinical approaches may provide important background data on the antinociceptive properties of HA. For instance, in horses, intraarticular injections of HA preparations attenuated the lameness in natural and experimentally induced OA [
19,
20]. In anesthetized cats and rodents HA preparations reduced inflammation- and OA-induced increases of neuronal discharges in nociceptive Aδ- and C-fibres innervating the knee joint [
21‐
24]. Herein we show an alternative preclinical approach to monitor long-term antinociceptive effects of HA preparations, namely the repetitive induction of short-lasting pain states in the joint by the injection of bradykinin, combined with prostaglandin E
2 (PGE
2) [
25,
26]. These inflammatory mediators sensitize nociceptive Aδ-and C-fibres to mechanical stimuli [
27‐
32], a basic mechanism for the occurrence of pain upon movements in the normal working range of the joint. Firstly, we validated the described bradykinin/PGE
2 model with regards to behavioral readout parameters in rats for a long-term study on the antinociceptive effects of stabilized hyaluronic acid from a non-animal source (NASHA) up to 56 days, and we established a dose-response relation for NASHA. Secondly, the obtained effective dose of NASHA was compared with two other clinically used preparations, that is Hylan GF20 and sodium hyaluronate, for duration and effect sizes of their antinociceptive properties.
NASHA is characterized by a gel structure which is stabilised using about 1% of cross-linking agent, thereby increasing the half-life time of the product in the joint compared with traditional HA preparations [
33,
34]. Thus fewer injections are necessary as compared with other compounds, which may reduce the risk of infection [
5]. The efficacy of NASHA has been well documented in clinical studies [
35]. Hylan GF20 is another HA product with a modified HA composition which is available as an intra-articular formulation for the treatment of OA. Here we report on the magnitude and long-term duration of antinociceptive effects of NASHA and other HA preparations in the bradykinin/PGE
2 model of repetitive joint pain.