Botulinum toxin for the treatment of chronic idiopathic constipation
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective is to assess the efficacy and safety of botulinum toxin for the treatment of chronic idiopathic constipation.
Background
Constipation is one of the most prevalent gastrointestinal complaints. It can be a symptom of metabolic or organic disease, or of defective extrinsic innervation of the colon, or it can be drug‐related. However, in many constipated patients no specific abnormalities can be found, in which case the constipation is referred to as idiopathic constipation. Primary or idiopathic constipation can be broadly divided into three subtypes, including slow transit constipation (i.e. colonic inertia), outlet delay constipation (i.e. obstructive defecation, pelvic floor dyssynergia, pelvic floor dysfunction, defecatory dysfunction, anismus), and functional constipation. Females, children and the elderly are more frequently affected with constipation (Heaton 1992; Johanson 1989; Nyam 1997). Although constipation is often considered to be a problem of low stool frequency, the symptomatology is far more complicated, and is subjective. The symptoms of constipation can also include difficulty in expelling the stool, a feeling of incomplete evacuation, abdominal bloating, discomfort and general malaise. Causes for chronic constipation are often multifactorial and may include endocrine or metabolic disorders, neurologic disorders, psychiatric disorders, and physical inactivity (Everhart 1989).
Description of the intervention
Both pharmacologic and nonpharmacologic measures have been used for treating primary or idiopathic constipation. Pharmacologic treatment of constipation has been traditionally based on osmotic or secretory laxatives and bulking agents. However, these therapies often fail, may have short‐lived efficacy and induce adverse events such as bloating and abdominal cramps. Other methods used for treating idiopathic constipation include: lubiprostone (Lang 2008), tegaserod (Kamm 2005), probiotics (De Paula 2008), colchicine (Verne 2003), and misoprostol (Roarty 1997).
When there is no response to medical treatment, some surgical treatment protocols may be used for the treatment of chronic idiopathic constipation including disimpaction of hard stool from the rectum under general anesthetic, formation of antegrade continent enema (ACE) stoma, excision of colon and/or megarectum and formation of a stoma, treatment by anal dilation or internal anal sphincter myectomy, or intra sphincteric injection of botulinum toxin.
How the intervention might work
Internal anal sphincter (IAS) myectomy has been performed on children to treat idiopathic constipation and constipation caused by IAS achalasia, intestinal neuronal dysplasia, and Hirschsprung's disease (Freeman 1984; De Caluwe 2001). However, the detrimental effect of any procedure that may weaken the anal sphincters permanently is unknown and may not become apparent for many years (Lunniss 2004).
Botulinum toxin injection has been used extensively and safely in children and adults in skeletal muscle for the treatment of strabismus and spacticity, and in smooth muscle for the treatment of achalasia of esophagus, anal fissure and anismus for intractable constipation. Local injection of botulinum toxin inhibits release of acetylcholine from presynaptic cholinergic nerves with an accompanying loss of junctional acetylcholine receptors which would result in loss of excitatory sympathetic input to IAS tone. It has been suggested that the major effect of botulinum toxin on the IAS is through blockade of sympathetic stimulation which is caused by reduction in noradrenaline release at the neuromuscular junction (Jones 2004).
Botulinum toxin reduces contraction of striated and smooth muscle in a focal and transient fashion and can be used repeatedly if necessary and it may provide the same effect as internal anal sphincter myectomy without the potential long‐term problem of permanent sphincter damage. Histologic examination of anal sphincter muscle in an animal model using botulinum toxin and saline injection has shown no evidence of damage to the sphincter compared with control (Langer 1997). The rationale for using botulinum toxin is that by the time the effect of toxin has worn off, which is approximately three months, the frequency and completeness of defecation and sensory awareness will have improved.
Why it is important to do this review
Botulinum toxin treatment for constipation remains controversial and data from the clinical setting have been scant to date. It is therefore necessary to carry out a systematic review to evaluate the effectiveness of botulinum toxin for the treatment of chronic idiopathic constipation to provide a more comprehensive understanding of the available data.
Objectives
The primary objective is to assess the efficacy and safety of botulinum toxin for the treatment of chronic idiopathic constipation.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials addressing the effectiveness of botulinum toxin for the treatment of chronic idiopathic constipation irrespective of blinding, language, and publication status will be considered for inclusion.
Types of participants
Studies which involved participants described as having a chronic idiopathic constipation will be included. Using the American College of Gastroenterology Chronic Constipation Task Force criteria chronic constipation can be defined as, "unsatisfactory defecation characterized by infrequent stools, difficult stool passage or both. Difficult stool passage includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/lumpy stools, prolonged time to stool, or need for manual maneuvers to pass stool (Brandt 2005)."
Types of interventions
The following types of interventions will be considered for inclusion:
1. Botulinum toxin injection into the internal anal sphincter versus myectomy of the internal anal sphincter; and
2. Botulinum toxin injection into the internal anal sphincter versus no intervention or placebo (sham injection).
Types of outcome measures
Primary outcomes
The primary outcome will be global improvement of clinical symptoms including but not limited to stool frequency, stool consistency, and abdominal pain (patient or physician evaluated).
Secondary outcomes
Secondary outcomes will include improvement in stool frequency, abdominal pain, abdominal distension, adverse events, and disease‐related quality of life.
Search methods for identification of studies
Electronic searches
The following electronic databases will be searched: Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE (1966‐ present), EMBASE (1980 ‐ present), and the IBD/FBD Group Specialised Register.
The following medical subject headings and/or key words and/or text words will be "constipation", "Botulinum toxin", "Internal anal sphincter myectomy", and the results were then combined with the Cochrane highly sensitive search strategies for identifying randomized trials.
Searching other resources
The references of identified trials and relevant review articles will be searched to identify further relevant trials.
Data collection and analysis
Selection of studies
Two authors will independently identify trials for inclusion based on the selection criteria described above. When it is unclear from the title or abstract if the paper fulfills the criteria, a copy will be obtained and the two authors will jointly decide if the study meets the inclusion criteria. Disagreement will be resolved by discussion and consensus with a third author (Hao XY).
Data extraction and management
Two authors will independently extract the following data from each study:
1. First author;
2. Year the study was conducted;
3. Year of publication;
4. Country;
5. Inclusion and exclusion criteria;
6. Baseline characteristics such as age, sex ratio, concurrent disease;
7. Description of interventions and number of participants in each group;
8. Primary and secondary outcomes;
9. Methodological quality;
10. Intention‐to‐treat analysis; and
11. Source of funding.
Any unclear or missing information will be sought by contacting the authors of the individual trials. If there is any doubt whether the trials share the same participants ‐ completely or partially (by identifying common authors and centres), the authors of the trials will be contacted to clarify whether the trial has been duplicated.
Differences in opinion will be resolved through discussion and consensus.
Assessment of risk of bias in included studies
Methodological quality will be defined as the confidence that the design and the report of the randomised clinical trial would restrict bias in the comparison of the intervention (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998 ; Kjaergard 2001; Wood 2008 ), the methodological quality of the trials will be assessed based on sequence generation, allocation concealment, blinding (of participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other sources of bias. Quality components will be classified as follows:
Two authors will independently assess the risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Factors to be assessed include:
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sequence generation (i.e. the allocation sequence was adequately generated);
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allocation sequence concealment (i.e. allocation was adequately concealed);
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blinding (i.e. knowledge of the allocated intervention was adequately prevented during the study);
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incomplete outcome data (i.e. incomplete outcome data were adequately addressed);
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selective outcome reporting (i.e. reports of the study are free of suggestion of selective outcome reporting?);
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baseline imbalance (i.e. there was no baseline imbalance in important characteristics);
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early stopping (i.e. a sample size calculation was reported and the trial was not stopped or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was low);
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academic bias (i.e. the author of the trial has not conducted previous trials addressing the same interventions);
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source of funding bias (i.e. funding did not come from any parties that might have a conflict of interest, e.g. a drug or a device manufacturer); and
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other potential sources of bias the study was free of other problems that could put it at a high risk of bias).
A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias. Disagreements will be resolved by consensus. Study authors will be contacted when insufficient information was provided to determine risk of bias.
Measures of treatment effect
The relative risk (RR) with 95% confidence intervals (95% CI) will be calculated for dichotomous outcomes. The weighted mean difference (WMD) with 95% CI will be calculated for continuous variables.
Unit of analysis issues
Non‐standard design randomised clinical trials may present statistical problems in this review. Whilst we do not anticipate cross‐over or cluster randomisation designs, we do expect multiple intervention groups. Care will be taken to avoid 'unit of analysis' errors when analysing these types of trials (Higgins 2008).
Dealing with missing data
The following strategy will be used when confronted with missing data. Original investigators will be contacted to request missing data. Two methods for dealing with missing data will be utilized if this approach fails. For example, the data will be assumed to be missing at random, or missing values will be assumed to have a negative outcome (e.g. treatment failure). Sensitivity analyses will be performed in these situations to assess how results change based on these assumptions. Finally, the potential impact of missing data on the findings of the review will be addressed in the Discussion section.
Assessment of heterogeneity
Heterogeneity will be explored using the chi‐square test (a P value of 0.10 will be regarded as statistically significant). The magnitude of heterogeneity will be assessed using the I2 measure (Higgins 2002). An I2 of 50% or more will be considered to represent moderate heterogeneity and in such cases a random effects model will be used for pooling data. Potential causes of heterogeneity will be explored by carrying out sensitivity and subgroup analyses.
Assessment of reporting biases
Reporting biases (e.g., publication, time lag, multiple publication) will be considered at all points of both data analysis and interpretation. If enough randomised clinical trials are identified in a particular field, attempts will be made to analyse for publication bias using funnel plots (Egger 1997; Macaskill 2001) bearing in mind that publication bias does not necessarily cause asymmetry.
Data synthesis
Data will be pooled for meta‐analysis if the participants, interventions and outcomes are comparable (based on author consensus). Meta‐analysis will be performed using the Review Manager 5.0 software provided by The Cochrane Collaboration (RevMan 2008). Data will be pooled using a fixed effects model (DeMets 1987). A random effects model will be used in the case of significant heterogeneity (DerSimonian 1986).
Outcomes will be presented in a descriptive way if meta‐analysis is considered to be inappropriate.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses based on types of interventions, treatment duration, and drug dosage will be explored.
Sensitivity analysis
Sensitivity analyses will examine the impact of the following variables on the pooled effect:
1. Random effects versus fixed effects modelling; and
2. Study quality.
