Botulinum Toxin in Pain-Related Post-Stroke Limb Spasticity: A Meta-Analysis of Early and Late Injections

Abstract

Spasticity is a common complication associated with stroke, and around 72% of stroke patients will develop pain during the disease. Botulinum toxin (BoNT) is a safe and efficacious treatment for spasticity and can improve associated complications, including pain. Hence, this meta-analysis aims to establish whether BoNT can reduce pain-related post-stroke spasticity (pPSS) in the early treatment period (<12 weeks post-stroke) or in the late period (>12 weeks post-stroke) based on the available evidence. This study also aims to establish the dose-response relationship of BoNT-A in pPSS. Based on pooled data from multiple studies, there is no significant difference in the scores measuring pPSS between patients who received early BoNT-A injections and those who received a placebo. This finding suggests that within the early treatment period, BoNT-A may not be more effective than a placebo in reducing pPSS. However, it is important to note that the data for early BoNT-A injections are limited, indicating that research is needed to draw definitive conclusions [z = 3.90 (p < 0.0001)]. While BoNT-A appears somewhat more effective than a placebo in the late phase, as indicated by the small to moderate positive z value, there is not enough evidence to confidently claim superiority over a placebo [z = 1.48 (p = 0.14)].

Keywords: botulinum toxin; early injection; late injection; pain-related post-stroke spasticity; spasticity.

Figure 1

PRISMA flow diagram depicting search for BoNT-A studies on pain-related post-stroke spasticity (pPSS).

Figure 2

Early BoNT-A studies in pain-related post-stroke spasticity [15,16,17].

Figure 3

Late BoNT-A studies on pain-related post-stroke spasticity [18,19,20,21,23,24,25,26].

Figure 4

Funnel plot of early BoNT-A injection studies.

Figure 5

Funnel plot of late BoNT-A injection studies.

Figure 6

BoNT-A mechanism of action in the neuromuscular junction. BoNT-A causing sodium (Na+) channel interference and the cleavage of SNAP 25, resulting in disruption of translocation of important proteins that promote pain generation.

Figure 7

Illustrated mechanism of BoNT-A on proposed pathophysiology of pPSS. In patients with stroke, the loss of inhibition of the stretch reflexes in the upper neurons results in spasticity. It is postulated that spasticity in prolonged cases can induce inflammation. Studies have shown that repeated inflammation can cause the release of peptides, including calcitonin gene-related peptide (CGRP) and Substance P. BoNT-A acts on the peripheral blockade of the CGRP, Substance P, and Glutamate receptors, which ultimately inhibits the central sensitization of pain.