What flexibility
of dose is permitted?
What form
of rescue medication is allowed, and when?
These
are linked questions. Clearly there has to be control over both
of these factors or it will be impossible to tell what has worked
for the patient. A commonly held view is that in a therapeutic
setting it is unreasonable to permit more than three days without
a bowel movement. Hence at this point an alternative laxative,
oral or rectal (perhaps better in terms of likely speed of effect
and of lack of carry-over effects), can be offered. The likelihood
of needing this intervention might be an outcome for a particular
dose of the test laxative, or it might be taken as a prompt
to increase the dose of the test agent to a pre-specified higher
level after which the sequence begins again.
Eligibility,
endpoints, and practical considerations
There
are problems in defining eligibility criteria and endpoints
for studies in constipation. For studies performed in a palliative
care population there are the added difficulties of a frail
and increasingly ill population whose unstable clinical state
introduces confounding variables and leads to significant attrition
of subject numbers.
An adequate
trial must also take account not only of the adverse effects of the therapeutic
interventions but also their acceptability to patients and their costs, which
vary considerably between different preparations. For outpatients, the cost of
admissions for constipation secondary to laxative failure is also an appropriate
outcome variable. Enemas and suppositories often involve staff in their administration,
and so here it is also appropriate to consider cost in terms of the time taken
to introduce them.
Even in chronic
constipation the number and quality of oral laxative trials is limited, and they
are difficult to compare as there is no standardization of approach, either in
design or in outcome measures.
- Design
- It is impossible to apply the same design to all treatment
settings. Consider the differences inherent in studying
constipation in:
- Home versus in-patient
- Nursing/medical visits
versus telephone monitoring
- Healthy patients versus
medically-ill patients
- Pediatric versus young
adult versus elderly adult, and
- Mentally clear versus mentally
impaired, and so on.
Outcome
measures - There remains a problem because there are
no particular endpoints, outcome measures, or scales that
have gained widespread acceptance.
Meta-analyses
of chronic constipation trials
Many trials
of rectal laxatives concentrate on their value for bowel preparation
prior to surgical or investigational procedures. Two systematic
reviews of oral laxatives in chronic constipation have been
published.
Table
8.2 Meta-analysis of oral laxatives for chronic
constipation
Click
each hyperlink for details
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- Identified
113 reports of which only 36 were of randomized
controlled trials considered suitable for analysis.
Of the 36 trials:
- 20
compared a single active agent (laxative or fiber)
to placebo, regular diet (or in one case yogurt)
or discontinued therapy.
- 16
compared active therapies: three were clearly
double-blinded, while the rest were certainly
or probably open.
- 20
studies permitted additional laxatives or enemas
if patients or clinicians deemed them appropriate,
and assessed their use as an outcome measure.
- Some
23 trials were under one month duration.
- Dropout
rates ranged from 0 to 60% with 17 trials losing
more than 20% of entrants.
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- Took studies identified in Tramonte's work and
also examined additional databases in order to
concentrate on the effectiveness of laxatives
in people over age 55 years. Twenty trials were
identified:
- One half (10) compared two active therapies
- The other half (10) compared one therapy against
placebo.
- Authors confirmed that the quality of many laxative
trials is mediocre.
- Authors concluded that while laxatives as a
class improve bowel function and symptoms of constipation,
there is little evidence of any preparation being
markedly more effective than any other.
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