Summer 2010 - The British Pain Society

I have to say that I can see no
'good' reason to support the
persistence of diamorphine
usage in the UK. I put 'good'
in apostrophes because I admit
it's a value judgement (there’s
no Cochrane-level review to
fall back on, sadly), but I have
tried to take a critical look at the
evidence base for the choices,
especially for palliative medicine.
My overall impression is that many
of the diamorphine aficionados in
palliative care are, in my opinion,
guided more by tradition and
misplaced concept of familiarity
taking precedence over innovation
and evidence. So why does
diamorphine hold this special
place in palliative care?
(There is also a case made for
its use in British anaesthetics,
but from my reading of that and
discussion with anaesthetists
both within the UK and outside
it, the scientific arguments for
continuation of diamorphine for
the spinal route are not rock-solid
– but more on that later.)
The tradition/familiarity argument
basically states that because
we've been doing something for
the last four decades, it must be
right. In my opinion, this is a very
poor reason to block progress
in medicine and I can't see that
principle being applied anywhere
else than in (British) end of life
care. Let’s go back to where it
started. Diamorphine was the
drug of choice at St Christopher's
in the early 1970s until Dr Robert
Twycross, even then, showed that
it was no better than morphine.
I quote from his seminal paper
(one of the first randomised
double-blind controlled trials
in palliative medicine) – “A
controlled trial of diamorphine
(diacetylmorphine, heroin) and
morphine is reported in which
the two drugs were administered
regularly by mouth in individually
determined effective analgesic
doses... 699 patients entered the
trial and, of these, 146 crossed
from diamorphine to morphine,
or vice versa, after about two
weeks using an oral potency ratio
of 1.5/1 determined in a pilot
trial... In the female crossover
patients, no difference was noted
in relation either to pain or the
other symptoms evaluated. On
the other hand, male crossover
patients experienced more pain,
and were more depressed,
while receiving diamorphine....
It is concluded that, provided
allowance is made for the
difference in potency, morphine
is a satisfactory substitute for
orally administered diamorphine.
However, when injections are
necessary, the greater solubility
of its hydrochloride gives
diamorphine an important
practical advantage over
morphine, especially when large
doses are required.” (Twycross
1977)
Thus, oral diamorphine was
found to be equivalent to oral
morphine – or actually worse for
males – but because of its greater
solubility (which is actually only
important for large doses given
by the parenteral route), it was
recommended over parenteral
morphine. Which could have
been the final word on the
subject – until alternatives to
both morphine and diamorphine
became available in the following
decades.
Twycross’ introduction reveals
more fascinating insight into the
thinking in palliative care in the
1970s - “Moreover, diamorphine
has been the strong analgesic of
choice at St. Christopher's Hospice
since its inception in 1967 on the
grounds that it: (1) causes less
nausea and vomiting; (2) often
results in a return of appetite
when given to patients with
anorexia; (3) is less constipating;
(4) enhances the mood of the
patient whereas morphine not
infrequently causes dysphoria; (5)
results in a patient who is more
alert, active and cooperative.”
Oddly for such a well-researched
paper, none of these assertions
about the ‘advantages’ of
diamorphine are referenced.
So they probably represent the
opinion of hospice workers
amassed over the previous ten
years – evidence grade IV, we
would say now. And interestingly
enough, reduced nausea is one
of the advantages of diamorphine
cited by the Home Office in its
consultation document. I cannot
find any authoritative source
for that, or the other alleged
advantages, apart from the greater
water solubility.
The only evidence I'm aware
of, that diamorphine may do
something ‘special’ as an opioid
analgesic is from the laboratory
of Gavril Pasternak in New York.
(Rossi et al, 1996) This group
identified a novel opioid receptor
to which diamorphine appeared
to be a direct ligand, that was
distinct from the mu-opioid
receptor (MOR) that was bound
by morphine. However, this new
splice variant of the MOR was
also bound by fentanyl and the
morphine metabolite M-6β-G,
so even this was not a ‘unique’
property of diamorphine. As far as
I know nobody else has replicated
this finding and all the other
evidence is that diamorphine only
works when it is de-acetylated to
morphine and then targets the
classical MOR. With diamorphine
we are therefore only using
a rapidly absorbed version of
morphine.
The issue about water solubility
is interesting. In the palliative
care world the key issue is for
use in subcutaneous injections
and infusions. Sometimes it is
both necessary and acceptable
to use fairly high doses of opioid
for these. (However, we would
now frown on the patients who
still occasionally turn up on
‘thousands’ of milligrams per day
of diamorphine or morphine – we
now understand that in those
cases, there is almost certainly
a large degree of tolerance and
probably also opioid-induced
hyperalgesia, which ‘feed’ the
vicious circle leading to ever
higher doses. (Chu et al, 2006;
Fallon, Colvin, 2008; Mao, 2008).
Up till 2009, I could not argue
against the superior solubility
of diamorphine – and with
heavy heart (!), I actually had
to convert some of my patients
from morphine or oxycodone
infusions to diamorphine for
just this reason. But since last
year we have oxycodone in high
concentration (50mg/ml) - and so
that major argument in favour of
diamorphine is now history. In the
past year I have never had need to
convert a patient to diamorphine
for the sake of fitting the dose
of opioid into a Graseby syringe
driver.
Admittedly the high strength
oxycodone costs more, but in
fact the current perverse situation
caused by the monopoly of the
manufacturer of diamorphine is
that the latter is now actually more
expensive than standard strength
oxycodone or morphine. But even
if oxycodone or morphine were
more expensive than diamorphine,
can we really justify saying that
palliative medicine prescribing
should be determined more by
cost to the NHS/hospice charities
than the quality of care? The
outcome for patients may well
be better with a more expensive
drug - and there is good enough
evidence that oxycodone causes
less CNS adverse effects like
hallucinations and sedation than
morphine (Mucci-LoRosso 1998;
Reid et al, 2006). In the final
analysis, the cost of oxycodone
concentrate for the last few days
is insignificant in comparison to
all the other costs that the health
service and charities throw at
patients in the last year of life.
For the past 20 years we have
course also been able to use
fentanyl or alfentanil, both very
potent drugs and with, at least for
the former in its transdermal patch
formulation, a very solid evidence
base of superiority over morphine
in terms of adverse effects, patient
convenience and preference
(Ahmedzai, Brooks 1997; Clark
et al 2004; Tassinari 2008). Both
drugs can also be given by the
parenteral route, where they are
acknowledged to be the safest
opioids to use in renal failure,
when diamorphine and morphine
are in fact dangerous on account
of their toxic metabolites.
PAI N N E W S S U M M E R 2010 43