Assessing adverse effects of intra-articular botulinum toxin A in healthy Beagle dogs: A placebo-controlled, blinded, randomized trial.

Helka M Heikkilä,Jouni Junnila,Outi Laitinen-Vapaavuori,Anna Hielm-Björkman,Pernilla Syrjä,Tarja S Jokinen,Louis S Premkumar

doi:10.1371/journal.pone.0191043

Abstract

ObjectiveTo investigate the clinical, cytological, and histopathological adverse effects of intra-articularly injected botulinum toxin A in dogs and to study whether the toxin spreads from the joint after the injection.MethodsA longitudinal, placebo-controlled, randomized clinical trial was conducted with six healthy laboratory Beagle dogs. Stifle joints were randomized to receive either 30 IU of onabotulinum toxin A or placebo in a 1:1 ratio. Adverse effects and spread of the toxin were examined by evaluating dynamic and static weight-bearing of the injected limbs, by assessing painless range of motion and pain on palpation of joints, and by performing synovial fluid analysis, neurological examination, and electrophysiological recordings at different examination time-points in a 12-week period after the injections. The dogs were then euthanized and autopsy and histopathological examination of joint structures and adjacent muscles and nerves were performed.ResultsIntra-articular botulinum toxin A did not cause local weakness or injection site pain. Instead, static weight-bearing and painless range of motion of stifle joints decreased in the placebo limbs. No clinically significant abnormalities associated with intra-articular botulinum toxin A were detected in the neurological examinations. Electrophysiological recordings showed low compound muscle action potentials in two dogs in the botulinum toxin A-injected limb. No significant changes were detected in the synovial fluid. Autopsy and histopathological examination of the joint and adjacent muscles and nerves did not reveal histopathological adverse effects of the toxin.ConclusionIntra-articular botulinum toxin A does not produce significant clinical, cytological, or histopathological adverse effects in healthy dogs. Based on the electrophysiological recordings, the toxin may spread from the joint, but its clinical impact seems to be low.

Highlights

Botulinum toxins are the strongest toxins known to man [1]
No clinically significant abnormalities associated with intra-articular botulinum toxin A were detected in the neurological examinations
No significant changes were detected in the synovial fluid

Summary

Introduction

Botulinum toxins are the strongest toxins known to man [1]. They are produced by the bacterium Clostridium botulinum in at least seven serotypes, with serotype A (BoNT/A) appearing to be the most potent [2,3]. Botulinum toxins inhibit acetylcholine release in the neuromuscular junction and in the cholinergic nerve terminals within the autonomic nervous system, which leads to paralysis of affected muscles and inhibition of secretion in affected glands [4]. These effects have been exploited in medicine, where intramuscular (IM) and subdermal BoNT injections have been used for treatment of various painful musculoskeletal conditions and hyperhidrosis already since the 1980s [5]. Intra-articular therapy is directly targeted to the painful joint, which reduces the systemic effects of the treatment and can lead to greater pain relief than systemic pain medication [9]. In our recent study, IA BoNT/A did not affect the concentration of substance P inside a joint

Methods

Results

Conclusion