Abstract
Background
This is an update of a Cochrane review first published in 2004, and previously updated in 2009 (no change in conclusions). Cervical dystonia is a frequent and disabling disorder characterised by painful involuntary head posturing. Botulinum toxin type A (BtA) is usually considered the first line therapy for this condition, although botulinum toxin type B (BtB) is an alternative option.
Objectives
To compare the efficacy, safety and tolerability of botulinum toxin type B (BtB) versus placebo in people with cervical dystonia.
Search methods
We identified studies for inclusion in the review using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists of articles and conference proceedings, last run in October 2015. We ran the search from 1977 to 2015. The search was unrestricted by language.
Selection criteria
Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtB versus placebo in adults with cervical dystonia.
Data collection and analysis
Two independent authors assessed records, selected included studies, extracted data using a paper pro forma and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third author. We performed one meta-analysis for the comparison BtB versus placebo. We used random-effects models when there was heterogeneity and fixed-effect models when there was no heterogeneity. In addition, we performed pre-specified subgroup analyses according to BtB doses and BtA previous clinical responsiveness. The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. The primary safety outcome was the number of participants with any adverse event.
Main results
We included four RCTs of moderate overall methodological quality, including 441 participants with cervical dystonia. Three studies excluded participants known to have poorer response to Bt treatment, therefore including an enriched population with a higher probability of benefiting from Bt treatment. None of the trials were independently funded. All RCTs evaluated the effect of a single Bt treatment session using doses between 2500 U and 10,000 U. BtB was associated with an improvement of 14.7% (95% CI 9.8% to 19.5) in the patients’ baseline clinical status as assessed by investigators, with reduction of 6.8 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-total score) at week 4 after injection (95% CI 4.54 to 9.01). Mean difference (MD) in TWSTRS-pain score at week 4 was 2.20 (95% CI 1.25 to 3.15). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups in the withdrawals rate due to adverse events or in the proportion of participants with adverse events. However, BtB-treated patients had a 7.65 (95% CI 2.75 to 21.32) and a 6.78 (95% CI 2.42 to 19.05) increased risk of treatment-related dry mouth and dysphagia, respectively. Statistical heterogeneity between studies was low to moderate for most outcomes. All tested dosages were efficacious against placebo without clear-cut evidence of a dose-response gradient. However, duration of effect (time until return to baseline TWSTRS-total score) and risk of dry mouth and dysphagia were greater in the subgroup of participants treated with higher BtB doses. Subgroup analysis showed a higher improvement with BtB among BtA-non-responsive participants, although there were no differences in the effect size between the BtA-responsive and non-responsive subgroups.
Authors’ conclusions
A single BtB-treatment session is associated with a significant and clinically relevant reduction of cervical dystonia impairment including severity, disability and pain, and is well tolerated, when compared with placebo. However, BtB-treated patients are at an increased risk of dry mouth and dysphagia. There are no data from RCTs evaluating the effectiveness and safety of repeated BtB injection cycles. There are no RCT data to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, and impact on quality of life.
Plain language summary
Botulinum toxin for people with involuntary posturing of the head
Undesired, uncontrollable, and often painful placement of the head, a disease called cervical dystonia or spasmodic torticollis, is a relatively uncommon condition (affecting 57 to 280 people per million) that can be very disabling and can compromise quality of life. Mostly the cause is unknown and no cure exists. As this is typically a chronic disease, it requires long-term treatment.
Botulinum toxin (Bt) is a natural powerful chemical produced by a bacterium called Clostridium botulinum, that can cause severe paralysis in animals and humans. It can also be used to treat many conditions, in particular those with involuntary muscle contractions, such as cervical dystonia, by delivering intra-muscular Bt injections. There are different types of Bt, not all available for therapeutic purposes. Bt type A (BtA) is normally the first-used treatment in cervical dystonia. However, not all patients respond to BtA injections, and in such situations, treatment with Bt type B (BtB) is of special interest.
This update of a previous Cochrane review aimed to assess the effectiveness (reduction in severity, disability and pain) and safety of BtB in cervical dystonia, in comparison to placebo (a pretend medicine).
We performed a literature search in October 2015 for studies that compared BtB with placebo in people with cervical dystonia.
We found four studies comparing a single BtB treatment session with placebo, including 441 participants in total.
There was moderate-quality evidence that a single BtB treatment session is efficacious when compared to placebo, improving cervical dystonia symptoms by between 10% and 20%. This clinical benefit applies to people with both a poor and a good response to previous BtA treatments. Both physicians and patients evaluated BtB positively. BtB-treated patients are, however, at an increased risk of dry mouth and swallowing difficulties.
Further studies are needed to establish the long-term clinical benefit of BtB treatment, including its impact on quality of life, to evaluate the best treatment intervals and doses, as well as to find out which people with cervical dystonia would benefit the most from BtB treatment.
