LONG-LASTING EFFECTS OF AN INTRA-ARTICULARLY ADMINISTERED BRADYKININ RECEPTOR INHIBITOR IN PATIENTS WITH KNEE OSTEOARTHRITIS

Abstract

Introduction: Bradykinin (BK) exerts its effects directly via B2 receptors but also indirectly through release of factors such as prostaglandins, cytokines, or histamine. During in vitro and preclinical in vivo studies, the B2 receptor inhibitor icatibant (ITB) has been shown to be a potent inhibitor of BK effects. Recently it has been found that a single injection of 90 μg of ITB significantly reduced pain in patients with knee OA, and this effect lasted for about 1 week. The aim of the present study was to determine whether ITB, by multiple dosing, may exert long-lasting clinically relevant effects on OA pain.

Objectives:

1. To compare the onset, extent and duration of pain relief (pain during activity, at rest and at night) in the affected knee between 2 dose groups of ITB and placebo by using a visual analogue scale (VAS).

2. To compare ITB and placebo for safety and the efficacy variables: Western Ontario McMaster Universities OA index (WOMAC), and time until need of rescue medication.

Study design: Randomised, double-blind, placebo-controlled, 3-arm, parallel-group, 12-week multi-centre study to compare the effect of intra-articular injections of 2 doses of ITB (500 μg and 2000 μg) and placebo in patients with symptomatic unilateral knee OA. Subjects were treated 3 times in weekly intervals and then followed-up for 10 weeks. Assessments of pain and intake of rescue medication was followed with an electronic patient diary on a daily basis. Functional assessment of the affected knee joint was performed by answering the WOMAC questionnaire at several visits following the last injection.

Statistical analysis included the Chi-square test, differences in means, Wilcoxon-test, the trapezoid rule and Kaplan-Meier curves, using analysis of variance without and with covariates (ANOVA, ANCOVA).

Results: 340 subjects were screened, and 266 were randomised and treated: 90 with placebo, 86 with 500 μg and 90 with 2000 μg ITB. Treatment-emergent adverse events were experienced by 13 subjects treated with placebo, 8 with 500 μg and 17 treated with 2000 μg ITB.

After 3 injections, long-lasting reduction in pain up to 12 weeks after start of treatment could be observed in all treatment groups. Onset of pain relief by _ 10 units was fast and had been reported already 4 hours after start of injection. Both ITB groups consistently demonstrated greater effects on pain when compared to the placebo group; however, there was no difference between the 500 μg and 2000 μg dose groups.

Conclusion: The outcome of the present study demonstrates ITB as an analgesic with fast onset and long-lasting pain relief, which could be differentiated against placebo. Its extent of pain relief, together with its excellent safety profile, qualifies ITB as a promising alternative for intervention in acute and chronic pain.