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Opioid tolerance
Does constipation
tolerance develop?
The
question arises as to whether tolerance to the constipating action
of morphine might arise just as it can do to its pain-relieving
action. Experimentally, mu2
receptor mediated opioid actions such as delaying of intestinal
transit show less development of tolerance than mu1
mediated analgesia does (Ling
et al., 1989).
In the larger
of the two palliative care studies mentioned above (Sykes,
1998), patients followed up for over two months (n=28) did not differ significantly
from the rest of the group in morphine or laxative consumption but did have higher
stool frequencies and somewhat lower use of enemas and suppositories. Their median
laxative dose had risen over the review period but by much less than had their
median morphine dose.
Twelve of Fallon
and Hanks' patients survived for six months. Among them were four who required
no laxatives despite taking morphine, sometimes in substantial amounts (Fallon
and Hanks, 1999). It is not clear whether these four patients had never needed
laxatives or whether they had at some point been able to give them up, i.e. whether
they had become tolerant to the constipating effect of morphine or whether they
lay at one extreme of the morphine dose-response curve for constipation.
It might be
expected that palliative care patients with a longer prognosis
would have milder constipation than those who are iller: they
will be eating and drinking more and they will be more mobile.
Thus, although it is possible that tolerance to the gut effects
of morphine does occur, the phenomenon has yet to be quantified.
Are synthetic
opioids more or less constipating?
As the range
of alternative strong opioids to morphine has increased there has been growing
interest in the possibility that some may cause less constipation. This is particularly
so of fentanyl in its transdermal formulation. Several crossover trials have reported
fentanyl to be less constipating than morphine, but a number have exhibited methodological
flaws in relying on subjective assessments of constipation without measuring laxative
intake. Also, different morphine: fentanyl dose conversion ratios have been used,
making it unclear whether or not the fentanyl dose truly matches the potency of
the morphine.
A
recent trial of fentanyl and morphine has addressed most of these
issues in using a relatively higher dose of fentanyl than some
others, obtaining stool frequency and consistency data from patient
diaries, and taking the as required use of laxatives (which are
detailed) as an outcome variable (Radbruch
et al., 2000). Over a 30 day study period laxative use was
significantly (p<0.001) less than during the preceding week
when morphine was being used, without any change in bowel movement
frequency.
Figure
7.4
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| Bowel
movements and use of laxatives. For each day the percentage
of patients using laxatives and of patients reporting
bowel movements is calculated for the 23 patients who
completed the study. Days -6 to 0: treatment with oral
slow-release morphine; days 1 to 30: treatment with
transdermal fentanyl |
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Figure
7.5
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| Laxatives
used by 23 patients (muliple entries). Days -6 to 0:
treatment with oral slow-release morphine; days 1 to
30: treatment with transdermal fentanyl. |
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Reduction
in laxative use has also been reported after changing from morphine
to methadone, but to date only on a case history basis (Daeninck
and Bruera et al., 1999). Clearly, formal trials are
needed.
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