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Alternative
approaches to trial design
In
the investigation of opioid-induced
constipation, two alternative approaches
to a comparative trial in frail patients
are:
- To
use members of methadone maintenance
programs as subjects (for example:
Cheskin
et al., 1995; Freedman
et al., 1997)
- To
mimic the condition in healthy volunteers
by giving them morphine (which clearly
can be done only for a brief period)
or loperamide, which acts at opioid
receptors in the gut but has very
limited oral bioavailability.
The
examples below illustrate the use
of these groups and also, in some
cases, the much-needed exploration
of novel laxative agents.
- Healthy
volunteers given morphine –
14 healthy volunteers received oral
and intravenous placebos and were
then randomized to receive intravenous
morphine (0.05 mg/kg) with either
oral placebo or oral methylnaltrexone
(19.2 mg/kg), a peripherally acting
opioid antagonist. The outcome measure
was small bowel transit time (SBTT),
assessed by the lactulose hydrogen
breath test. Morphine significantly
extended the SBTT in the presence
of placebo, but in the presence
of methylnaltrexone the SBTT did
not differ from baseline (Yuan
et al., 1997).
- Methadone
maintenance subjects – The same
investigators gave methylnaltrexone
or placebo intravenously in a randomized
double-blind fashion to 11 patients
on a methadone maintenance program
who complained of constipation associated
with their methadone treatment.
Methylnaltrexone shortened SBTT
by 78 minutes, whereas placebo shortened
it by 1 minute (p<0.001) (Yuan
et al., 2000).
- Methadone
maintenance subjects, triple crossover design – 57 methadone
maintenance patients were randomized in a triple crossover study
changing between no treatment (one week), placebo, lactulose
and polyethylene glycol solution (PEG) (each for two weeks).
Outcome measures were bowel movement frequency (self reported),
stool consistency and ease of defecation. Both lactulose and
PEG were better than placebo or no treatment.Adverse effects
were most common with PEG but not significantly more than control.
PEG was proposed to be the most cost-effective (Freedman
et al., 1997)
|
Table
8.4 Efficacy Detrmination - Stool Consistency
|
|---|
| | Control
| Placebo
| Lactulose
| Polyethylene
Glycol 3350 Solution
|
|---|
Weekly
Stools
Hard
Soft
Loose
Adverse Reactions
Frequency of excess gas/week
Severe cramping/week |
2.08 ± 0.27
1.48 ± 0.31
0.09 ± 0.04
2.83 ± 0.42
1.72 ± 0.31
|
1.75 ± 0.24
3.27 ± 0.46†
1.47 ± 0.51‡
2.96 ± 0.43
2.13 ± 0.42
|
0.98 ± 0.23*
3.39 ± 0.35†
1.43 ± 0.26‡
3.60 ± 0.41
1.49 ± 0.27
|
1.06 ± 0.18*
3.57 ± 0.44†
2.24 ± .034§
4.06 ± 0.53||
2.09 ± 0.38||
|
Values
are presented as the weekly stool mean ± SEM
*P < 0.003, compared with control.
†P
< 0.001, compared with control.
‡P < 0.01, compared with control.
§P < 0.0001, compared with control.
|| Not significant compared with control. |
|
| Figure
8.3 Number of stools/week. Ctrl-h; plac, placebo; lact,
lactulose; PEG, polyethylene glycol. |
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