Adverse Event Profiles of High Dose Botulinum Toxin Injections for Spasticity

Abstract

Background Botulinum toxin injections are effective in relieving focal spasticity resulting from upper motor neuron injuries. Doses approved in the United States for onabotulinumtoxinA and incobotulinumtoxinA are up to 400 units, yet higher doses are often used. Objective To determine differences in risk of adverse events when using higher (>600 units) as compared to lower doses within clinically applicable categories; the difference in adverse events between types of botulinum toxin‐A, and any association of the injection of cervical muscles with increased risk for adverse events. Design and Setting Retrospective analysis of injections performed over a 3‐year period at a freestanding rehabilitation hospital network. Participants Persons with spasticity or dystonia undergoing ona‐ and/or incobotulinumtoxinA injections. Interventions Not applicable. Main Outcome Measures Adverse events for injections were divided into the three dose ranges (≤400 units, 401‐600 units, or > 600 units). Results 889 injections in 342 patients met inclusion criteria with 65% ≤400 units, 21% 401‐600 units, and 14% >600 units. Adverse events were not significantly increased in doses of 401‐600 units relative to ≤400 units (OR 0.97, 95% CI 0.31, 2.98). Doses of toxin over 600 units were associated with significantly increased relative risk of adverse events (OR 2.98, 95% CI 1.12, 8.13). There were no significant differences between adverse event rates for onabotulinumtoxinA or incobotulinumtoxinA (P >.99). Inclusion of cervical muscles in isolation did significantly increase the risk of adverse events (OR 4.21, 95% CI 1.15, 15.46). Conclusion Risk for adverse events were not significantly increased in doses of ona‐ and/or incobotulinumtoxinA up to 600 units, suggesting that the current 400 units upper bound of approved dose may need to be reexamined. Doses above 600 units were found to increase the rate of adverse effects and clinical benefit versus risk should be taken into account. Level of Evidence III.

High Dosage of Botulinum Toxin Type A in Adult Subjects with Spasticity Following Acquired Central Nervous System Damage: Where Are We at?

“…In this study, 155 subjects were enrolled, but only 11 (7.1%) suffered from traumatic brain injury [38]. The remaining two investigations did not report the number of spastic subjects according to aetiology [39] or spasticity aetiology [29]. Since these studies had mixed samples, the investigation by Ianieri et al was described in the stroke paragraph and that by Kirshblum et al was reported in the paragraph concerning studies with mixed samples.…”

“…Of studies that enrolled mixed samples, mild AEs consisting of generalised weakness (12%), feeling of residual urine (10%), constipation (9%) and blurred vision (8%) were observed by Dressler et al, but these disturbances were attributed to underlying neurological conditions and not to the effect of BTX-A [11]. The study by Kirshblum et al analysed if adverse events increased when injecting higher doses of BTX-A, and if onaBTX-A or incoBTX-A differed in adverse event rates [29]. They reported that AEs did not increase until doses of BTX-A exceeded 600 U. AEs were observed in 7 subjects (5.6%), 4 (2.2%) and 16 (2.6%) treated by ≤400U; 400-600 U and >600 U of BTX-A, respectively.…”

“…BTX-A formulation alone or associated with other treatments were injected in three and eight studies for onaBTX-A and incoBTX-A, respectively. Two studies used both onaBTX-A and incoBTX-A formulations [28,29]. High-dosage aboBTX-A was described in only one study.…”

“…No effect was observed [28]. The latter by Kirshblum S et al [29] was a retrospective study to determine differences in risk of AEs when using doses higher that 600 U of onaBTX-A or incoBTX-A as compared to lower doses. The study investigated a large sample of 342 subjects suffering from dystonia and spasticity, but only 42 patients received doses higher than 600 U.…”

“…Given that it predominantly enrolled subjects with brain injury, the study by Intiso et al has been described in the related section above [43]. Likewise, the study by Kirshblum S et al that injected subjects with dystonia and spasticity has been reported under the stroke subheading [29].…”