Review Systematic review of the role of alternative application routes for opioid treatment for moderate to severe cancer pain: An EPCRC opioid guidelines project Palliative Medicine 25(5) 578–596 ! The Author(s) 2010 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269216310383739 pmj.sagepub.com Lukas Radbruch University of Bonn, Department of Palliative Medicine, Bonn, and Centre of Palliative Medicine, Malteser Hospital Bonn, Germany Peter Trottenberg RWTH Aachen University, Department of Palliative Medicine, Aachen, Germany Frank Elsner RWTH Aachen University, Department of Palliative Medicine, Aachen, Germany Stein Kaasa Norwegian University of Science and Technology, Trondheim, Norway Augusto Caraceni National Cancer Institute, Department of Palliative Medicine, Milan, Italy Abstract The European Palliative Care Research Collaboration is updating the EAPC recommendations on opioids in cancer pain management. A systematic literature search on Medline on the use of alternative routes for opioid application identified 242 papers, with 72 publications included in the final evaluation. Two or more alternative routes of opioid application were compared in 18 papers with a total of 674 patients. The best evidence base was available for the subcutaneous route. A comparison of subcutaneous and intravenous routes found no differences, confirming both routes as feasible, effective and safe. Efficacy and safety of the rectal route was comparable to the parenteral route. The side effect profile seemed to be very similar for the subcutaneous, intravenous, rectal or transdermal routes. Local side effects were reported for rectal application as well as for subcutaneous and transdermal administration. In conclusion, the systematic review found good evidence that subcutaneous administration of morphine or other opioids is an effective alternative for cancer patients if oral treatment is not possible. However, for a number of patients intravenous, rectal or transdermal therapy will offer a good alternative to the subcutaneous route. The review found no significant differences in efficacy or side effects between the alternative application routes. Keywords Neoplasm, pain, opioids Background Oral opioids have been recommended as the mainstay of cancer pain management, most prominently in the recommendations of the World Health Organization. 1–3 The recommendations of the European Association for Palliative Care (EAPC) on the use of morphine and other opioids in 2001 also considered oral opioids as the first-line approach to cancer pain. 4 However, if patients are unable to take opioids orally the recommendations listed subcutaneous appli- cation as the preferred alternative, as it is simpler and less painful than intramuscular injections. This was graded as a rather weak recommendation, based on expert opinion rather than on controlled trials. The recommendations also suggested that opioids other than morphine such as diamorphine or hydromorphone may be preferred for parenteral administration, as they are more soluble than morphine and thus smaller injec- tion volumes are necessary. However, this would be subject to availability, which differs in the European countries. Transdermal application also was listed as an alternative in the recommendations, if patients have stable opioid dose requirements, and rectal appli- cation for those patients who prefer that route. Corresponding author: Univ.-Prof. Dr Lukas Radbruch, Department of Palliative Medicine, University Hospital Bonn, 53127 Bonn, Germany Email: [email protected]
Transcript
Review
Systematic review of the role ofalternative application routes for opioidtreatment for moderate to severe cancerpain: An EPCRC opioid guidelines project
Palliative Medicine
25(5) 578–596
! The Author(s) 2010
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0269216310383739
pmj.sagepub.com
Lukas Radbruch University of Bonn, Department of Palliative Medicine, Bonn, and Centre of Palliative Medicine, Malteser Hospital Bonn, Germany
Peter Trottenberg RWTH Aachen University, Department of Palliative Medicine, Aachen, Germany
Frank Elsner RWTH Aachen University, Department of Palliative Medicine, Aachen, Germany
Stein Kaasa Norwegian University of Science and Technology, Trondheim, Norway
Augusto Caraceni National Cancer Institute, Department of Palliative Medicine, Milan, Italy
Abstract
The European Palliative Care Research Collaboration is updating the EAPC recommendations on opioids in cancer pain
management. A systematic literature search on Medline on the use of alternative routes for opioid application identified
242 papers, with 72 publications included in the final evaluation. Two or more alternative routes of opioid application
were compared in 18 papers with a total of 674 patients. The best evidence base was available for the subcutaneous
route. A comparison of subcutaneous and intravenous routes found no differences, confirming both routes as feasible,
effective and safe. Efficacy and safety of the rectal route was comparable to the parenteral route. The side effect profile
seemed to be very similar for the subcutaneous, intravenous, rectal or transdermal routes. Local side effects were
reported for rectal application as well as for subcutaneous and transdermal administration. In conclusion, the systematic
review found good evidence that subcutaneous administration of morphine or other opioids is an effective alternative for
cancer patients if oral treatment is not possible. However, for a number of patients intravenous, rectal or transdermal
therapy will offer a good alternative to the subcutaneous route. The review found no significant differences in efficacy or
side effects between the alternative application routes.
Keywords
Neoplasm, pain, opioids
Background
Oral opioids have been recommended as the mainstayof cancer pain management, most prominentlyin the recommendations of the World HealthOrganization.1–3 The recommendations of theEuropean Association for Palliative Care (EAPC) onthe use of morphine and other opioids in 2001 alsoconsidered oral opioids as the first-line approach tocancer pain.4
However, if patients are unable to take opioidsorally the recommendations listed subcutaneous appli-cation as the preferred alternative, as it is simpler and
less painful than intramuscular injections. This wasgraded as a rather weak recommendation, based onexpert opinion rather than on controlled trials. Therecommendations also suggested that opioids otherthan morphine such as diamorphine or hydromorphonemay be preferred for parenteral administration, as theyare more soluble than morphine and thus smaller injec-tion volumes are necessary. However, this would besubject to availability, which differs in the Europeancountries. Transdermal application also was listed asan alternative in the recommendations, if patientshave stable opioid dose requirements, and rectal appli-cation for those patients who prefer that route.
Corresponding author:
Univ.-Prof. Dr Lukas Radbruch, Department of Palliative Medicine, University Hospital Bonn, 53127 Bonn, Germany
Subcutaneous injection would result in a more rapidonset of analgesia than oral administration, with peakplasma concentrations achieved within 15–30minutes.Owing to the low bioavailability with oral administra-tion of morphine, the conversion ratio of oral to sub-cutaneous or to intravenous application was estimatedin the recommendations as between 2 : 1 and 3 : 1.However, this also was graded as a weak recommenda-tion, with no published research to support it. The rec-ommendations stated that the relative potency ratio oforal to parenteral morphine has been highly controver-sial, and seems to vary considerably not only interindi-vidually, but also according to the circumstances inwhich the opioid is used.
For continuous parenteral application subcutaneousinfusion was recommended, preferably with portablesyringe driver pumps. Intravenous opioid infusionwas named as an alternative for patients who alreadyhave an indwelling intravenous line, and transdermalopioid therapy could be a useful non-invasive alterna-tive. Again this recommendation was graded as weak.
Buccal, sublingual and nebulized routes of adminis-tration of morphine were not recommended because atthat time there was no evidence of clinical advantageover the conventional routes. However, sublingualbuprenorphine was recommended as a useful alterna-tive to low-dose oral morphine for patients who havedifficulty in swallowing.
Surveys on clinical practice have shown that physi-cians often prefer other strategies. In a US study thepercentage of patients on intravenous opioid therapywas increased from 33% to 55% after admission tothe cancer pain service.5 However, until the time ofdischarge 57% of patients received opioids via the oralroute, 18% intravenous, but also 18% transdermaland 5% subcutaneous application. Convenience, butalso non-invasiveness, the need for rapid effect,impaired gastrointestinal function and intolerance oforal opioids were named as reasons for the preferenceof a specific route. More recently, a telephone surveyon medication kits for managing symptomaticemergencies in the home found oral, sublingual andrectal routes of administration as common.6 However,these preferences may have been due to the setting ofemergency interventions by hospice nurses, but notby physicians.
A Japanese survey7 found that physicians used theoral route most frequently for patients receiving homecare and requiring morphine, with the rectal routebeing second in frequency. Rectal application wasprescribed by more than 80% of the physicians in thissurvey, whereas subcutaneous application was used byonly 44% and intravenous by 4%. Hospital-basedphysicians used the subcutaneous route much morefrequently than physicians working at clinics.
From Europe, an older Swedish nationwide surveyreported a preference of intermittent subcutaneous orintramuscular injections of morphine and less frequentuse of continuous intravenous or subcutaneous infu-sions or intermittent injections via an indwelling but-terfly needle.8 A recent German survey from a Berlinhome care service explained that in the last days of life45% of the patients were treated with subcutaneousinjections or infusions.9 Intravenous opioid applicationwas performed in 13% of the patients, and the rest ofthe patients were divided evenly between oral andtransdermal opioid administration. However, reasonsfor specific preferences for any routes were not pro-vided. An Italian survey on all opioid prescriptionsfor cancer patients in the Venetian region found only21% of all patients dying from cancer had been pre-scribed opioids.10 From these patients 64% were trea-ted with oral morphine, 5% with injectable morphine,23% with transdermal fentanyl and 8% with sublingualbuprenorphine.
Considering the survey results from clinical practiceand the introduction of new therapeutic systems withopioids such as new patch systems or intranasal sprayswith fentanyl it seems necessary to update the EAPCrecommendations.11 The revision of the recommenda-tions will be based on systematic reviews to providehigh-level evidence-based guidelines. This guidelinework is part of the European Palliative Care ResearchCollaborative (EPCRC), an international collaborativeaiming to produce clinical guidelines on pain, depres-sion and cachexia.12
For this review, the use of alternative routes foropioid application if patients are unable to take mor-phine orally are evaluated for efficacy and safety in asystematic literature review. An overlap with thereviews of transdermal fentanyl and transdermal bupre-norphine, with review the on breakthrough pain as wellas with the review on equianalgesic dose ratios is to beexpected. This review focuses on studies where two ormore application routes are compared, preferably withthe same opioid used for both routes.
Methods
This review is part of a series of literature reviews thatwill be used to revise the guidelines of the EAPC onopioid management in cancer pain and followed theprotocol provided for this series (see http://www.epcrc.org). The remit for this review asked for the eval-uation of alternative routes for opioid application inadult patients with moderate to severe pain directlydue to cancer, and who are unable to take oral opioids.The evaluation should investigate whether there isany evidence to support the use of one alternativeroute (transdermal, parenteral, rectal, subcutaneous,
Radbruch et al. 579
intravenous, oral transmucosal and nasal) over anotherin the management of pain.
We performed a systematic literature review inMedline (PubMed) with a search strategy that wascoordinated with that provided in the series protocoland with those of other reviews in the guidelinerevision. In correlation with the template the searchwas restricted to publication in English language andto the time period from 1966 to July 2009. The searchtemplate was modified to retrieve only publicationsthat included two alternative routes (Table 1).The comparisons covered by the search strategy areshown in Table 2.
Eligibility for assessment was performed by one ofthe authors (LR). Publications were excluded if theyreported on animals, on children or on non-cancerpatients. Studies testing drugs other than opioids were
also excluded, as were studies on postoperative pain,even if they had recruited cancer patients.Breakthrough pain is a subject for a separate systematicreview, so these studies were considered for inclusiononly if they described treatment of pain exacerbationsor tried to influence baseline pain levels as well. Non-systematic reviews were also excluded. Surveys on clin-ical practice, for example as a questionnaire survey onthe use of subcutaneous infusions, were also excluded.
Studies were included if they allowed for a compar-ison of two different application routes, either fromswitching routes or from different cohorts of patients.Individual case reports and case series were consideredonly for evaluation of safety and toxicity, but not forevaluation of efficacy. Studies on pharmacokinetics orreports on plasma concentrations were not considered,if they did not include clinical data on efficacy or safety.
Table 1. Search strategy for Medline
Search Queries Result
#9 Search #7 AND #8 Limits: Publication Date from 1966 to 2009/07/30, English 242
#8 Search morphine OR hydromorphone OR oxycodone OR fentanyl OR buprenorphine OR methadone
OR polamidon* OR Levomethadone OR palladon OR oxycodon OR durogesic OR transtec OR actiq
OR effentora OR temgesic OR dilaudid OR instanyl OR abstral Limits: Publication Date from 1966 to
2009/07/30, English
60,471
#7 Search #4 AND #5 Limits: Publication Date from 1966 to 2009/07/30, English 513
#6 Search #4 AND #5 608
#5 Search (subcutaneous* AND intravenous*) OR (intravenous* AND transdermal) OR (subcutaneous*
AND transdermal) OR ((transmucosal OR buccal OR sublingual) AND (transdermal OR subcutane-
ous* OR intravenous* OR parenteral OR intranasal OR rectal)) OR (intranasal* AND (transdermal OR
subcutaneous* OR intravenous* OR parenteral OR rectal)) OR (rectal AND (transdermal OR sub-
cutaneous* OR intravenous* OR parenteral)) OR (parenteral AND (transdermal OR subcutaneous*
OR intravenous*))
37,859
#4 Search (#1 OR #2) AND #3 64,865
#3 Search pain 414,626
#2 Search cancer OR neoplasm OR tumour OR oncol* OR carcinoma* OR malignan* 26,18,090
#1 Search palliative care OR hospice OR terminal care OR terminally ill 71,909
Table 2. Comparison of application routes (white boxes indicate the comparisons of alternative application routes that were
Information on analgesic effectiveness and on safetywas extracted from the studies and entered into aspreadsheet. The data record form included trialdesign, patient number and diagnoses, opioid andapplication route, indicators on effectiveness andsafety as well as the results reported for these parame-ters. The data record form was based on the templateprovided in the review series.
Sources of bias were collected and provided as notesin the data form. Bias was not assessed systematically,as the review included not only randomized, but alsonon-randomized controlled trials. The review also didnot investigate the risk of bias across studies.
Meta-analysis was not planned for this review, as ascoping review had shown that the differences in theoutcome indicators used in the studies would preventa meaningful compilation of results. Moreover, withthe number of comparisons required, the number ofcontrolled studies available for each comparison wasexpected to be small.
Results
The search strategy retrieved 242 studies. Excludingpublications on paediatric palliative care or on non-cancer patients, in animals or testing drugs other thanopioids or publications on pharmacokinetics that didnot report data on efficacy or safety left 72 studies.These were evaluated in more detail. Eighteen ofthese studies including a total of 674 patientscompared two or more alternative routes of opioids
application (Figure 1). Intravenous or subcutaneousapplication was more frequently one comparator thanother alternative routes of administration. In additionto these studies three systematic review included resultsthat were relevant for this review.13–15
Subcutaneous route
A recent systematic review13 evaluated Medline publi-cations for the time period of 1975 to 2002. Two retro-spective surveys with 82 patients16,17 and 9 prospectivetrials with a total of 244 patients,18–26 8 of them con-trolled trials, using either crossover or parallel groupdesign. One of these studies compared subcutaneousapplication of fentanyl with that of morphine,18
another one hydromorphone and morphine.20 No dif-ferences in efficacy were reported in these two trials.Two trials with morphine19,21 and one with hydromor-phone25 compare subcutaneous with other parenteralor spinal application routes. Three trials evaluate dif-ferent application regimes such as patient-controlledwith continuous infusion.22–24 Again no differencesare described. One observational study confirmed thefeasibility of the subcutaneous route even for extendedperiods.26
Similarly, the Cochrane review on hydromorphoneby Quigley14 included 12 studies in chronic pain,and five of these studies with a total of 177 patientsused alternative routes. The author reported nodifference between subcutaneous and intravenousroute in one study,25 between continuous infusion or
242 studies
12 studies
72 studies
4 studies
18 studies
7 studies 12 studies 1 study
Studies identified with the search strategy in PubMed
Studies screened after exclusion of reports on children, non-cancer patients,pharmacokinetic studies
Studies comparing two alternative routes
3 reviews
Subcutaneous Sublingual/transmucosal
Systematic reviews
Intravenous Rectal Transdermal
Figure 1. Flowchart for the literature review (multiple entries).
Radbruch et al. 581
patient-controlled analgesia via the subcutaneous routein two studies22,23 or between subcutaneous infusionswith morphine or hydromorphone.20 The fifth studycompared intramuscular application of hydromor-phone with morphine,27 again with no differencesbetween drugs.
In our systematic review the search strategy identi-fied 11 studies with 466 patients which compared dif-ferent application routes (Table 3). Four of the thesestudies compared subcutaneous with intravenous appli-cation,25,28–30 in three studies with morphine, in theother with hydromorphone. In the study of Moulinet al.,25 a 48-hour infusion with hydromorphone wastested in a controlled crossover comparison, finding nodifference in efficacy or side effects. Elsner et al.28 com-pared both routes for opioid titration for severe painexacerbations, finding similar efficacy and only a ten-dency for faster onset with intravenous titration. In thisstudy (as well as in the others) the small sample sizewith n¼ 39 could have masked significant differences,as the power analysis showed that a sample size ofn¼ 80 would have resulted in significance of the differ-ence. Drexel29 combined results from two small studiesin their report, with a change from subcutaneous appli-cation to intravenous in one study and from intrave-nous to subcutaneous in the other. No differences werefound for pain relief, quality of life or side effects.Koshy et al.30 compared two groups of patients receiv-ing either subcutaneous or intravenous infusions in aresource poor setting, and reported no differences inefficacy or safety, even if no pump systems were used.
The study of Bruera et al.31 used a crossover methodto compare rectal application of morphine with thesubcutaneous route. With an equianalgesic ratio of2.4:1 (rectal:subcutaneous) similar efficacy and sideeffects were reported for both routes, and the authorsconcluded that the rectal application is a reliable andnon-invasive alternative for patients who are not ableto take oral medications. In a second study from thesame group patients who were treated with subcutane-ous application of hydromorphone were switched eitherto oral or rectal methadone.32 In this study the switchto rectal application of methadone was twice as fast asthe oral route.
The other six studies used a sequential switch fromintravenous application to subcutaneous21,33,34 or fromtransdermal to subcutaneous.17,35,36 In the latter threestudies fentanyl, sufentanil, diamorphine and hydro-morphone were used for subcutaneous application.All studies reported good analgesic efficacy with subcu-taneous application. The study of Walsh et al.34 foundbetter pain relief in patients switched from intravenousto oral application than in those switched from intra-venous to subcutaneous, but this may have been relatedto different indications for these switches, as the study
described prescribing patterns and did not use a con-trolled methodology. In a retrospective evaluation ofpatients on the Liverpool Care Pathway of the Dyingmatched pairs were built for patients on transdermalfentanyl and those on subcutaneous diamorphine.36
The authors found no significant differences betweengroups, and good pain control in both. In all studieslocal toxicity at the needle insertion site was docu-mented only in a few cases. The incidence of systematicside effects was comparable between intravenous andsubcutaneous application21 and symptom control wasconsiderably improved after patients were switchedover to subcutaneous from oral or transdermalpretreatment.35
Another 24 studies including 1102 patients wereidentified that reported on subcutaneous applicationof opioids, using a wide range of opioids such as mor-phine, oxycodone, hydromorphone, diamorphine, fen-tanyl, sufentanil, methadone or ketobemidone. Localtoxicity at the needle insertion site was reported infre-quently with erythema, swelling, bleeding and subcuta-neous plaques. Systematic side effects were as expectedwith opioid treatment, most often with constipation,nausea and drowsiness.
In the studies comparing intravenous with subcuta-neous application of the same opioid, analgesic effectivedoses were similar for both routes. Conversion factorshave been described in some studies, but mostly onlycalculated from small numbers of patients and oftenwith a wide range and differences in different studies.For subcutaneous morphine to oxycodone a conversionfactor of 1.2� 0.4 and for subcutaneous hydromor-phone to oxycodone 0.5� 0.4).37 These conversion fac-tors are slightly different from the equivalentconversion factors of the oral application of the sameopioids. In another study the conversion factor wasdescribed as 1.2� 1.3 for subcutaneous hydromor-phone to oral methadone and 3� 2 for subcutaneoushydromorphone to rectal methadone.32 This is differentto the conversion factor of subcutaneous hydromor-phone to oral methadone of 0.93, and of subcutaneoushydromorphone to rectal methadone of 0.53 found inanother study.38
Intravenous route
In the Cochrane review on hydromorphone byQuigley14 only one of 12 studies in chronic pain usedthe intravenous route. In this study the authorsreported no difference between subcutaneous and intra-venous route.25
The literature search identified 12 studies with296 patients comparing intravenous with otherroutes of application (Table 4). Seven of thesestudies21,25,28–30,33,34 compared intravenous with
582 Palliative Medicine 25(5)
Tab
le3.
Studie
sco
mpar
ing
subcu
taneous
with
oth
er
applic
atio
nro
ute
s
stceffe edis :stluseR
yca ci ffe : stlu seR
Fir
stau
tho
r,
year
S
tudy
desi
gn
Pat
ient
num
bers
R
out
e D
rugs
Out
com
ea
mea
sure
s S
umm
ary
of r
esul
ts
Out
com
em
easu
res
Sum
mar
y o
fre
sult
s
Nar
rati
ve s
umm
ary
of r
esul
ts
No
tes
And
erso
n 20
04
Syst
emic
re
view
9
stud
ies
(326
pa
tient
s)
sc
Mor
phin
e,
hydr
omor
phon
e,
fent
anyl
Mis
cella
neou
s C
ontin
uous
sc
infu
sion
is
effic
ient
M
isce
llane
ous
Con
tinuo
us s
c in
fusi
on is
saf
e M
edlin
e re
sear
ch 1
975–
2002
, 9 p
rosp
ectiv
e an
d 2
retr
ospe
ctiv
e st
udie
s,
cont
inuo
us s
c in
fusi
on is
sa
fe a
nd e
ffect
ive,
no
maj
or d
iffer
ence
s be
twee
n op
ioid
s or
ap
plic
atio
n re
gim
ens
Lim
ited
to
Engl
ish
lang
uage
and
hum
an
Qui
gley
20
02Sy
stem
ic
revi
ew
5 st
udie
s (1
77
patie
nts)
sc, i
v, im
H
ydro
mor
phon
e,
mor
phin
e
Mis
cella
neou
s N
o di
ffere
nce
betw
een
rout
es o
r ap
plic
atio
n m
ode
Not
re
port
ed
Not
rep
orte
d Se
arch
unt
il N
ovem
ber
2006
, 12
stud
ies
on
chro
nic
pain
, 5 w
ith
alte
rnat
ive
rout
es, n
o di
ffere
nce
repo
rted
for
one
stud
y co
mpa
ring
iv
vers
us s
c, 2
stu
dies
co
mpa
ring
pat
ient
s-co
ntro
lled
appl
icat
ion
vers
us c
ontin
uous
in
fusi
on o
r 2
stud
ies
com
pari
ng
hydr
omor
phon
e w
ith
mor
phin
e (o
ne s
tudy
im,
one
stud
y sc
)
Elsn
er
2005
C
ontr
olle
d co
hort
stu
dy,
rand
omiz
ed
39
iv (
21
patie
nts)
ve
rsus
sc
(18
)
Mor
phin
e V
AS
pain
in
tens
ity
(0=
no
pain
, 10
= w
orst
pai
n),
VR
S pa
in
inte
nsity
(no
, sl
ight
, m
oder
ate,
se
vere
, ver
y se
vere
, un
bear
able
pa
in),
%T
OT
PAR
%T
OT
PAR
31%
(iv
) 15
%
(sc)
, VA
S pa
in in
tens
ity
redu
ced
from
83±
17 t
o 32
±23
(iv
) an
d fr
om
68±
24 t
o 42
±27
(sc
)
Not
re
port
ed
Not
rep
orte
d T
itrat
ion
dose
s 4-
34 m
g (iv
) an
d 10
-200
mg
(sc)
. N
o si
gnifi
cant
diff
eren
ce
in m
ean
time
to r
each
ad
equa
te a
nalg
esia
with
53
min
utes
(iv
) an
d 77
m
inut
es (
sc).
Ada
ptat
ion
of c
ontin
uous
opi
oid
dosa
ge fo
llow
ing
titra
tion
and
calc
ulat
ion
of
conv
ersi
on fa
ctor
in 1
0 pa
tient
s (iv
) an
d 8
patie
nts
(sc)
: con
vers
ion
fact
or 6
.6±
7.9
(iv)
and
3.7±
3.3
(sc)
. Bot
h ro
utes
ar
e ad
equa
te t
o an
tago
nize
pai
n ex
acer
batio
ns q
uick
ly
and
adap
t th
e do
sage
of
cont
inuo
us m
edic
atio
n.
Pow
er a
naly
sis
repo
rted
, fo
r fa
ster
ons
et 2
x40
patie
nts
wou
ld h
ave
been
ne
eded
, for
%T
OT
PAR
po
wer
was
0.8
1
Pat
ient
s
(continued)
Radbruch et al. 583
Tab
le3.
Continued
Kos
hy
2005
C
ontr
olle
d co
hort
stu
dy,
non-
blin
ded
30
sc
vers
us iv
M
orph
ine
VA
S pa
in
inte
nsity
(0-
10)
Mea
n di
ffere
nce
VA
S pa
in a
fter
24
hour
s no
di
ffere
nce
betw
een
grou
ps (
sc 7
.1±
1.4,
iv
7.6±
1.3)
Seda
tion
scor
e (n
o de
tails
pr
ovid
ed)
Seda
tion
scor
e no
di
ffere
nce
betw
een
grou
ps, b
oth
grou
ps s
igni
fican
t im
prov
emen
t, no
da
ta p
rovi
ded.
V
omiti
ng, n
ause
a an
d pr
uritu
s ab
sent
Con
tinuo
us in
fusi
on
eith
er s
c or
iv w
as
effe
ctiv
e an
d sa
fe,
with
out
use
of p
ump
syst
ems,
onl
y w
ith
beds
ide
drip
(co
st-
effe
ctiv
e)
Mou
lin
1991
C
ross
over
ra
ndom
ized
co
ntro
lled
15
sc
vers
us iv
H
ydro
mor
-ph
one
VA
S pa
in
inte
nsity
, pai
n re
lief (
0-10
0)
Mea
n V
AS
pain
inte
nsity
re
duce
d fr
om
appr
oxim
atel
y 31
to
20
in b
oth
grou
ps, p
ain
relie
f app
roxi
mat
ely
72 in
bo
th g
roup
s at
the
end
of
infu
sion
VA
S se
datio
n,
moo
d (0
-100
)
Mea
n V
AS
seda
tion
appr
oxim
atel
y 37
(s
c) a
nd 5
0 (iv
, not
si
gnifi
cant
), m
ood
appr
oxim
atel
y 72
(s
c) a
nd 5
8 (iv
, not
si
gnifi
cant
)
53 p
atie
nts
with
in
dica
tion
for
sc
appl
icat
ion,
20
incl
uded
, da
ta a
vaila
ble
for
15
patie
nts.
Infu
sion
for
48
hour
s, w
asho
ut w
ith
mor
phin
e, t
hen
48 h
ours
w
ith o
ther
dru
g, d
oubl
e du
mm
y te
chni
que.
In
fusi
on r
ates
1-3
5 m
g/h,
pa
in in
tens
ity, p
ain
relie
f, m
ood
and
seda
tion
sign
ifica
ntly
impr
oved
w
ith n
o di
ffere
nce
betw
een
sc a
nd iv
. Be
caus
e of
sim
plic
ity,
tech
nica
l adv
anta
ges
and
cost
-effe
ctiv
enes
s of
sc
infu
sion
iv s
houl
d be
ab
ando
ned
No
sign
ifica
nt d
iffer
ence
in
plas
ma
conc
entr
atio
ns
Brue
ra
1995
C
ross
over
, ra
ndom
ized
tr
ial,
non-
blin
ded
23
Rec
tal
vers
us
sc
Mor
phin
e V
AS
pain
in
tens
ity
(0-1
00),
VR
S (6
-ste
p, fr
om
McG
ill)
pain
in
tens
ity
Mea
n V
AS
pain
inte
nsity
no
diff
eren
ce (
rect
al
13.2
, sub
cuta
neou
sly
13.3
), m
ean
VR
S m
inim
al
diffe
renc
e (r
ecta
l 0.7
, su
bcut
aneo
usly
0.9
, p=
0.04
59)
VA
S na
usea
, se
datio
n (0
-100
)
VA
S se
datio
n no
di
ffere
nce
(rec
tal
23.2
, su
bcut
aneo
usly
24
.5),
VA
S na
usea
no
diff
eren
ce
(rec
tal 7
.8,
subc
utan
eous
ly 9
.0)
Mea
n do
sage
326
±69
mg
(rec
tal)
and
138 ±
28 m
g (s
ubcu
tane
ous)
, 12-
hour
in
terv
als
appr
opri
ate
with
rec
tal a
pplic
atio
n of
sl
ow-r
elea
se m
orph
ine,
re
ctal
app
licat
ion
is a
re
liabl
e, n
onin
vasi
ve
alte
rnat
ive
for
subc
utan
eous
app
licat
ion
Mea
n co
nver
sion
rat
ion
rect
al: s
ubcu
tane
ous
was
2.
4:1;
pow
er a
naly
sis
incl
uded
: 24
patie
nts
80%
po
wer
Dre
xel
1991
C
ross
over
no
n-ra
ndom
ized
co
ntro
lled
stud
y
15
sc
vers
us iv
M
orph
ine
Pain
sco
re,
qual
ity o
f life
sc
ore,
no
deta
ils o
n sc
ores
re
port
ed
Mor
phin
e do
sage
id
entic
al fo
r sc
and
iv
rout
e, (
73±
41 m
g/d)
, pa
in 2
.2 ±
1.1
for
sc,
2.1±
1.1
for
iv, q
ualit
y of
lif
e in
dex
2.9±
2.3
for
sc,
3.1±
2.3
for
iv
No
info
rmat
ion
No
diffe
renc
e in
si
de e
ffect
s 8
patie
nts
with
iv-in
fusi
on
(cro
ssed
ove
r to
sc-
pum
p),
7 pa
tient
s w
ith s
c-pu
mp
(cro
ssed
ove
r to
iv
-infu
sion
s). S
o in
all
15
patie
nts
at le
ast
72 h
of
iv-in
fusi
on c
ompa
red
to
2-20
wee
ks o
f sc
-pum
p. N
o di
ffere
nce
was
foun
d in
pai
n re
lief,
qual
ity o
f life
or
side
effe
cts
Com
bina
tion
of d
ata
from
tw
o pr
evio
us p
ublic
atio
ns:
Dex
el e
t al
. 198
5 an
d D
exel
et
al.
1989
stceffe edis :stluseR
yca ci ffe : stlu seR
Fir
stau
tho
r,
year
S
tudy
desi
gn
Pat
ient
num
bers
R
out
e D
rugs
Out
com
ea
mea
sure
s S
umm
ary
of r
esul
ts
Out
com
em
easu
res
Sum
mar
y o
fre
sult
s
Nar
rati
ve s
umm
ary
of r
esul
ts
No
tes
Pat
ient
s
584 Palliative Medicine 25(5)
Cam
pbel
l 19
83
Cas
e re
port
s 1
iv s
witc
h
to s
c M
orph
ine
Not
rep
orte
d Eq
ually
suc
cess
ful p
ain
cont
rol w
ith s
c an
d iv
N
ot
repo
rted
M
ild c
onst
ipat
ion,
lo
cal e
ryth
ema
at
inje
ctio
n si
te w
ith
sc r
oute
switc
hed
from
iv t
o sc
ro
ute,
2 m
onth
s fo
llow
up
Wal
sh
2006
C
ase
seri
es,
pros
pect
ive
50
iv t
o or
al (
17 p
atie
nts)
, iv
to
sc (
16 p
atie
nts)
, iv
onl
y (9
pat
ient
s), s
con
ly (
3 pa
tient
s), m
isce
lla
neou
s (5
pat
ient
s)
Mor
phin
e Pa
in c
ontr
ol
(goo
d/po
or)
Pain
con
trol
iv t
o or
al:
82/1
8% (
good
/poo
r), i
v to
sc
75/1
3%, i
v on
ly
67/2
%, s
c 33
/67%
, mis
c 10
0/0%
Not
re
port
ed
Not
rep
orte
d iv
to
oral
had
mor
es
stab
le p
ain
cont
rol
asse
ssed
with
a v
arie
ty o
f m
easu
res
Brue
ra
1995
C
ontr
olle
d co
hort
stu
dy,
non-
rand
omiz
ed,
open
37
All
patie
nts
pret
reat
men
t w
ith s
c, c
hang
e to
oral
(21
pat
ient
s)ve
rsus
rec
tal (
16)
Hyd
rom
orph
one
(pre
trea
tmen
t),
chan
ge t
om
etha
done
VA
S pa
in
inte
nsity
(0
-100
)
VA
S pa
in in
tens
ity
redu
ced
from
50±
21
(pre
trea
tmen
t w
ith
hydr
omor
phon
e) t
o 29
±13
(re
ctal
m
etha
done
) an
d fr
om
51±
23 (
pret
reat
men
t w
ith h
ydro
mor
phon
e) t
o 39
±25
(or
al m
etha
done
). T
otal
cos
t 86
±12
8 C
anad
ian
fund
s (r
ecta
l) ve
rsus
228
±25
3 (o
ral),
m
uch
high
er w
ith s
c hy
drom
orph
one
pret
reat
men
t
Not
re
port
ed
Mild
sed
atio
n an
d co
nstip
atio
n in
all
patie
nts,
oth
er s
ide
effe
cts
not
repo
rted
sep
arat
ely
for
rect
al r
oute
Mea
n tim
e fo
r ch
ange
ov
er fr
om p
retr
eatm
ent
with
sc
3.2 ±
3.7
days
for
rect
al r
oute
, 6.5
±3.
6 da
ys fo
r or
al. S
low
sw
itch
to m
etha
done
ei
ther
rec
tally
or
oral
ly
was
saf
e, e
ffect
ive
and
a lo
w c
ost
alte
rnat
ive
Con
vers
ion
fact
or
1.2±
1.3
for
sc
hydr
omor
phon
e/o
ral m
etha
done
and
3±2
for
sc
hydr
omor
phon
e to
rec
tal
met
hado
ne
Nel
son
1997
C
ross
over
, no
n-ra
ndom
ized
tr
ial
40
iv
switc
hed
to s
c M
orph
ine
VA
S pa
in
inte
nsity
, VR
S pa
in in
tens
ity
(non
e, m
ild,
mod
erat
e,
seve
re)
VA
S 22
.9±
21.6
(iv
) to
17
.6±
15.5
(sc
) V
RS
side
ef
fect
s (n
one,
m
ild,
mod
erat
e,
seve
re)
Loca
l tox
icity
2
patie
nts
(sc)
, no
sign
ifica
nt
diffe
renc
e in
sid
e ef
fect
s.
Con
stip
atio
n (iv
25
patie
nts,
sc
24),
dry
mou
th (
iv 2
3, s
c an
xiet
y/de
pres
sion
(iv
6, s
c 6)
, blu
rred
vi
sion
(iv
4, s
c 1)
, eu
phor
ia (
iv 3
, sc
2),
myo
clon
us
(iv 3
, sc
2), n
ause
a/vo
miti
ng (
iv 3
, sc
4),
rash
/pru
ritu
s (iv
3, s
c 0)
, re
spir
ator
y de
pres
sion
(iv
3, s
c 1)
, uri
nary
re
tent
ion
(iv 1
, sc
1) 2
1),
seda
tion
(iv10
, sc
7),
Dos
age
5.05
±4.
75 m
g/h
(iv)
to 5
.7±
5.8
(sc)
, 8/4
0 pa
tient
s di
d no
t ac
hiev
e st
able
dos
age,
all
in a
ll sc
no
t di
ffere
nt t
o iv
(continued)
Radbruch et al. 585
Tab
le3.
Continued
obse
rvat
ion
peri
ods,
no
diffe
renc
e fo
r th
e ot
her
10 p
erio
ds
Ove
rall
little
diff
eren
ce
betw
een
grou
ps, g
ood
pain
con
trol
in b
oth
grou
ps
Wat
anab
e 19
98
tran
sder
mal
sw
itch
to s
c
Fent
anyl
V
AS
pain
in
tens
ity
3/5
patie
nts
switc
hed
from
tra
nsde
rmal
to
sc
fent
anyl
goo
d pa
in r
elie
f (V
AS
53±
15 t
o 10
±10
), th
e ot
her
2 sw
itche
d to
ot
her
opio
ids.
10/
17
patie
nts
switc
hed
from
ot
her
opio
ids
to s
c fe
ntan
yl g
ood
pain
rel
ief
(VA
S 41
±24
to
33±
16)
Not
re
port
ed
Not
rep
orte
d fo
r tr
ansd
erm
al t
o sc
fe
ntan
yl, f
or o
ther
pa
tient
s im
prov
emen
t of
to
xici
ty in
7/1
0 pa
tient
s
3/5
patie
nts
switc
hed
from
tra
nsde
rmal
to
sc
fent
anyl
goo
d pa
in r
elie
f (V
AS
53±
15 t
o 10
±10
), th
e ot
her
2 sw
itche
d to
ot
her
opio
ids.
10/
17
patie
nts
switc
hed
from
ot
her
opio
ids
to s
c fe
ntan
yl g
ood
pain
rel
ief
(VA
S 41
±24
to
33±
16)
6 pa
tient
s st
abili
zed
on s
c fe
ntan
yl s
witc
hed
to
tran
sder
mal
fent
anyl
, 4
with
goo
d ef
fect
Entin
g 20
02
Cas
e se
ries
22
O
ral,
Cas
e se
ries
10
0
Ora
l (4
4),
tran
sder
mal
(56
) sw
itche
d to
sc
Mor
phin
e,
fent
anyl
, su
fent
anyl
, hy
drom
orph
one
NR
S 11
-ste
p,
clin
ical
ly
impo
rtan
t im
prov
emen
t (<
2 di
ffere
nce
on N
RS,
m
oder
ate
pain
or
less
)
Pain
inte
nsity
at
rest
de
crea
sed
from
6.3
to
4.4
afte
r 48
hou
rs a
nd
furt
her
to 3
.4 a
t th
e en
d of
tre
atm
ent,
impo
rtan
t im
prov
emen
t of
pai
n at
re
st fo
r 52
% o
f pat
ient
s af
ter
48 h
ours
and
for
71%
at
end
of t
reat
men
t, im
port
ant
impr
ovem
ent
of p
ain
duri
ng m
ovem
ent
for
43%
aft
er 4
8 ho
urs
and
61%
at
end
of
trea
tmen
t
VR
S 4-
step
fo
r na
usea
or
emes
is,
cons
tipat
ion,
co
nfus
ion,
ha
lluci
natio
ns,
som
nole
nce
Res
olut
ion
or
impr
ovem
ent
of
side
effe
cts:
na
usea
/em
esis
20
/33
patie
nts,
co
nstip
atio
n 34
/50,
so
mno
lenc
e 27
/45,
co
nfus
ion
13/1
5,
hallu
cina
tions
7/1
0,
any
side
effe
ct
25/7
8
Goo
d im
prov
emen
t in
ef
ficac
y an
d re
duct
ion
of
side
effe
ct fo
llow
ing
switc
h to
par
ente
ral
opio
ids
Not
cle
ar h
ow m
any
patie
nts
rece
ived
sc
or iv
ap
plic
atio
n
Elle
rsha
w
2002
C
ontr
olle
d co
hort
stu
dy,
retr
ospe
ctiv
e ev
alua
tion
94
Tra
nsde
rmal
(47
pa
tient
s),
sc (
47)
Fent
anyl
(47
pa
tient
s),
diam
orph
ine
(47)
Pain
(c
ontr
olle
d/un
cont
rolle
d)
Freq
uenc
y of
con
trol
led
pain
obs
erva
tions
dur
ing
last
48
hour
s si
gnifi
cant
ly
high
er fo
r tr
ansd
erm
al
fent
anyl
for
2/12
Not
re
port
ed
Not
rep
orte
d R
etro
spec
tive
eval
uatio
n,
mat
ched
pai
r bu
ildin
g fo
r th
e tw
o gr
oups
, med
ian
dosa
ge fe
ntan
yl 5
0 m
g,
diam
orph
ine
30 m
g.
stceffe edis :stluseR
yca ci ffe : stlu seR
Fir
stau
tho
r,
year
S
tudy
desi
gn
Pat
ient
num
bers
R
out
e D
rugs
Out
com
ea
mea
sure
s S
umm
ary
of r
esul
ts
Out
com
em
easu
res
Sum
mar
y o
fre
sult
s
Nar
rati
ve s
umm
ary
of r
esul
ts
No
tes
Pat
ient
s
sc,
subcu
taneous;
iv,in
trav
enous;
im,in
tram
usc
ula
r;VA
S,V
isual
Anal
ogu
eSc
ale;V
RS,
Verb
alR
atin
gSc
ale;N
RS,
Num
eri
calR
atin
gSc
ale.
586 Palliative Medicine 25(5)
Tab
le4.
Studie
sco
mpar
ing
intr
avenous
with
oth
er
applic
atio
nro
ute
s
Fir
stau
tho
r,
year
S
tudy
desi
gn
Pat
ient
num
bers
Elsn
er 2
005
Dre
xel 1
991
Kos
hy 2
005
Mou
lin 1
991
Nel
son
1997
C
ampb
ell
1983
W
alsh
200
6 Le
ow 1
995
Kor
nick
20
01
to
Kor
nick
20
03
st ceff e edis :st luseR
y cac if fe :stlus eR
stne itaP
Ro
ute
Dru
gs
Out
com
em
easu
res
Sum
mar
y o
f res
ults
Out
com
e m
easu
res
Sum
mar
y o
f res
ults
Nar
rati
ve s
umm
ary
of r
esul
ts
No
tes
See
Tab
le 3
39
Mor
phin
e
Se
e T
able
3
15
M
orph
ine
See
Tab
le 3
30
Mor
phin
e
See
Tab
le 3
15
Hyd
rom
orph
one
See
Tab
le 3
40
Mor
phin
e
Se
e T
able
3
1
Mor
phin
e
See
Tab
le 3
50
M
orph
ine
Cas
e se
ries
12
iv v
ersu
s
rect
ally
O
xyco
done
Pa
in in
tens
ity
VA
S V
AS
pre
5.7±
2.0
/ 4
.7±
2.2
(iv/r
ecta
l);
30 m
in 0
.4±
0.6
/ 2.
4±1.
8; 6
0 m
in
0.4±
1.2
/ 0.7
±0.
8;
120
min
1.3
±1.
8 /
0.5±
0.5;
240
min
2.
0±2.
3 / 0
.4±
0.4
VR
S 4-
step
fo
r dr
owsi
ness
, lig
hthe
aded
ness
, na
usea
, vo
miti
ng,
prur
itus,
sw
eatin
g
Dro
wsi
ness
and
lig
hthe
aded
ness
mos
t fr
eque
nt, n
ause
a m
ore
ofte
n w
ith r
ecta
l ad
min
istr
atio
n
Both
rou
tes
prov
ided
sa
tisfa
ctor
y an
alge
sia,
m
uch
mor
e ra
pid
on
set
with
iv(5
-8 m
in fo
r 25
%
pain
red
uctio
n)
vers
us r
ecta
l (6
0-12
0 m
in)
Onl
y si
ngle
dos
e
Cas
e se
ries
15
iv s
witc
h
tran
sder
mal
Fent
anyl
Pa
in in
tens
ity
at r
est
/ with
m
ovem
ent
11-s
tep
NR
S,
satis
fact
ion
with
cur
rent
le
vel o
f pai
n re
lief (
yes/
no)
Med
ian
pain
at
rest
re
duce
d af
ter
24
hour
s fr
om N
RS
3 to
2,
med
ian
pain
with
m
ovem
ent
from
4 t
o 3
Seda
tion
4-st
ep V
RS,
ot
her
adve
rse
effe
cts
seve
rity
on
4-s
tep
VR
S
Med
ian
seda
tion
redu
ced
from
VR
S 1
to 0
aft
er 2
4 ho
urs
Stab
le
conv
ersi
on
poss
ible
Not
eno
ugh
info
rmat
ion
to
calc
ulat
e co
nver
sion
fa
ctor
Cas
e se
ries
9
Tra
nsde
rmal
sw
itch
to iv
Fent
anyl
Pa
in in
tens
ity
at r
est
/ with
m
ovem
ent
11-s
tep
NR
S
Pain
>8
befo
re s
witc
h (in
clus
ion
crite
rion
) re
duce
d to
<4
(at
rest
) w
ithin
5 d
ays
in
all 9
pat
ient
s. 3
pa
tient
s sw
itche
d ba
ck
beca
use
of in
adeq
uate
pa
in r
elie
f with
m
ovem
ent
Seda
tion
4-st
ep V
RS,
ot
her
adve
rse
effe
cts
seve
rity
on
4-s
tep
VR
S
Seda
tion
incr
ease
d in
on
e pa
tient
D
osag
e w
as
high
er a
fter
sw
itchi
ng t
o iv
ap
plic
atio
n, b
ut
with
sup
erio
r pa
in r
elie
f. M
edia
n tim
e to
ach
ieve
m
ild le
vels
of p
ain
at r
est
was
1.5
day
s,si
x pa
tient
s ac
hiev
ed
mild
leve
ls o
f pai
n w
ith m
ovem
ent
with
in 3
day
s.
Not
eno
ugh
info
rmat
ion
to
calc
ulat
e co
nver
sion
fa
ctor
Zec
h 19
92
Se
quen
tial
coho
rt
stud
y
20Fe
ntan
yl
VA
S pa
in
inte
nsity
, VR
S pa
in r
elie
f (5
-ste
p)
VA
S pa
in in
tens
ity
decr
ease
d fr
om 6
8 to
34
on
day
1 (w
ith iv
PC
A)
and
furt
her
to
VA
S sy
mpt
om
inte
nsity
(0
=ne
ver/
not
at a
ll, 1
00=
no s
igni
fican
t di
ffere
nces
in s
ide
effe
cts
with
VA
S co
nstip
atio
n 31
±35
Intr
aven
ous
titra
tion
with
fe
ntan
yl
prov
ided
rap
id
Con
vers
ion
ratio
iv
: tra
nsde
rmal
1:
1 us
ed
tran
sder
mal
iv
to
(continued)
Radbruch et al. 587
Tab
le4.
Continued
effe
ctiv
e
Gro
nd
1997
Se
quen
tial
coho
rt
stud
y
50
iv,
tran
sder
mal
in
tens
ity
(0=
no p
ain,
00
= p
ain
as
bad
as c
an b
e)
VA
S pa
in in
tens
ity
redu
ced
from
ap
prox
imat
ely
44
(pre
trea
tmen
t, C
I 38–
50)
to 3
2 (d
ay 1
with
iv,
CI 2
7–37
) to
22
(day
2 w
ith t
rans
derm
al,
CI 1
7–27
), 17
on
day
7 an
d fin
ally
13
duri
ng
long
-ter
m t
reat
men
t (d
ay 8
5-53
5)
Perc
enta
ge o
f da
ys w
ith
sym
ptom
No
seve
re s
ide
effe
cts,
9
patie
nts
loca
l sid
e ef
fect
s (r
ashe
s or
pr
uritu
s). P
erce
ntag
e of
tre
atm
ent
days
for
cons
tipat
ion
redu
ced
from
40
(pre
trea
tmen
t) t
o 18
(t
itrat
ion
peri
od)
to
10 (
long
-ter
m),
dry
mou
th 4
2 to
53
5o 3
4,
naus
ea fr
om 3
4 to
17
to 1
7, d
yspn
oea
from
14
to
15 t
o 17
, so
mno
lenc
e fr
om 6
4 to
48
to 5
8, s
wea
ting
from
30
to 2
6 to
28,
ve
rtig
o fr
om 1
8 to
12
to 5
, vom
iting
from
18
to 1
1 to
5, d
iarr
hoea
fr
om 6
to
5 to
4,
prur
itus
from
2 t
o 7
to 2
. Res
pira
tory
rat
es
< 8
in 3
pat
ient
s.
Dro
pout
s be
caus
e of
su
rgic
al in
terv
entio
n (7
pat
ient
s), p
oor
com
plia
nce
(6),
inad
equa
te p
ain
relie
f(4
), re
spir
ator
y de
pres
sion
(1)
, pa
in r
elie
f with
ra
diot
hera
py (
1),
refe
rral
to
othe
r ho
spita
l (1)
Tre
atm
ent
dura
tion
3-53
5 da
ys, d
osag
e in
crea
sed
from
3.
1+2.
2 m
g/d
in
first
wee
k to
7.
8+2.
6 in
45t
h w
eek.
Iv t
itrat
ion
was
use
ful f
or
dose
find
ing,
and
tr
ansd
erm
al
appl
icat
ion
safe
an
d ef
fect
ive
Con
vers
ion
ratio
fo
1:1
.5 u
sed
from
iv t
o tr
ansd
erm
al, b
ut
3 pa
tient
s w
ith
resp
irat
ory
rate
<8/
min
ute,
so
1:1
is s
afer
fo
r co
nver
sion
Fent
anyl
V
AS
pain
26 (
tran
sder
mal
), th
en
incr
ease
d ag
ain
to 3
1 on
day
7.
extr
emel
y/al
l th
e tim
e)
(day
0)
to 2
2 ±34
(d
ay1)
to
13±
27
(day
7),
VA
S na
usea
4 ±
10, 6
±23
, 2±
9,
VA
S fa
tigue
38±
36,
28±
36, 2
6±35
, VA
S sw
eatin
g 22
±33
, 25±
27,
14±
16
relie
f, co
nver
sion
fr
om in
trav
enou
s to
tra
nsde
rmal
w
as s
afe
and
Fir
stau
tho
r,
year
S
tudy
desi
gn
Pat
ient
num
bers
stceff e e dis :st luseR
ycac if fe :stlus eR
stne itaP
Ro
ute
Dru
gs
Out
com
em
easu
res
Sum
mar
y o
f res
ults
Out
com
e m
easu
res
Sum
mar
y o
f res
ults
Nar
rati
ve s
umm
ary
of r
esul
ts
No
tes
iv,in
trav
enous;
VA
S,V
isual
Anal
ogu
eSc
ale;V
RS,
Verb
alR
atin
gSc
ale;N
RS,
Num
eri
calR
atin
gSc
ale.
588 Palliative Medicine 25(5)
subcutaneous application, including two studies with arandomized controlled methodology.25,28 As describedin the section on subcutaneous application, no differ-ences were reported between these two routes.
Only one study compared intravenous and rectalopioid application,39 finding no difference in painrelief, but faster onset of analgesia with the intravenousroute. Pain relief of 25% was achieved in 5–8minuteswith intravenous application compared with60–120minutes with rectal application. However, thisstudy included only 12 patients and a single dose appli-cation of oxycodone.
A comparison of intravenous and transdermal routefor opioid application was possible for four studies,predominantly because intravenous titration was usedfor dose finding before the initiation of transdermaltherapy. Only one study reported conversion fromtransdermal to intravenous application.40 The ninepatients in this study were suffering from severe painin spite of transdermal treatment. Following the switchto intravenous application higher dosages of fentanylwere required, resulting in superior pain relief with onlymild pain at rest after 1.5 days and good pain relief withmovement in six of the nine patients.
The other three studies used intravenous applicationof fentanyl before patients were switched to transder-mal application.41–43 All three studies reported goodpain relief compared with pretreatment and stable anal-gesia after switching to transdermal application. Sideeffects were reduced with intravenous applicationcompared with pretreatment regimens. Lower sedationscores were reported in all three studies, less constipa-tion in two41,43 and less dry mouth and vertigo in one.41
Less nausea was reported in one study41 and slightlyhigher intensity of nausea in another.43
A conversion ratio for oral:intravenous morphinebetween 2 : 1 and 3 : 1 is backed up by some papers,who reported a conversion of 2.9.44 For fentanyl thestudy of Zech et al.43 has used a 1 : 1 conversion ratiofrom intravenous to transdermal with comparable effi-cacy and tolerability. The subsequent study of Grondet al.41 used a higher conversion ratio of 1 : 1.5, butfound some complications with respiratory depressionwith this ratio, and concluded that the 1 : 1 ratio wouldbe preferable.
The literature search identified another nine studieswith a total of 549 patients reporting on the use of theintravenous application route with morphine, hydro-morphone and in some cases also methadone or oxy-codone. The survey from Meuret and Jocham45
reported on 143 patients treated with either subcutane-ous or intravenous application for treatment durationsof up to 437 days, using patients controlled analgesiawith morphine with good effect. Only 4% of patientsreported insufficient pain relief. However, results from
both application routes are not reported separately,and so comparison of adverse effects was not possible.Constipation, fatigue and nausea were predominant forthe whole set of patients. Ferris et al.46 published aretrospective evaluation of 135 patients treated eitherwith subcutaneous or intravenous application ofmorphine or hydromorphone for more than 6 days,with 35 patients receiving opioids via both routes.Again data were not reported separately for the appli-cation routes, good efficacy was seen with both routesand the profile of adverse events was similar to otheropioid surveys.
Rectal route
The Cochrane review from Wiffen and McQuay15
included two studies comparing oral with rectal appli-cation of morphine.47,48 However, one study was pub-lished in Japanese.47 The other study with 34 patientsreported that pain relief was achieved significantlyfaster and was maintained better in the rectal group.47
The literature search in this study identified fourstudies with 174 patients that compared alternativeapplication routes, using morphine, oxycodone ormethadone (Table 5). The studies of Bruera et al.31
and of Leow et al.39 reporting similar efficacy and tol-erability with subcutaneous or intravenous applicationhave been described in detail above. The workgroup ofBruera32 also switched patients pretreated with subcu-taneous hydromorphone to either oral or rectal meth-adone and found that both routes were safe andeffective, but that the mean time for change was muchshorter for rectal compared with oral application.Pannuti et al.49 also found similar efficacy with oral,rectal and sublingual application of morphine in a con-trolled study with 102 patients who received treatmentfor at least 10 days. Drowsiness and dry mouth werereported more often with the rectal application, andtwo patients discontinued rectal application due tolocal intolerance. However, the patient group withrectal application reported the highest reduction ofpain intensity.
Only one study reported a conversion ratio with2.4:1 as the ratio of rectal : subcutaneous morphine.31
The literature search also found another two studieswith 56 patients reporting on the rectal application ofmorphine or methadone, but without a comparison ofalternative routes.
Transdermal route
In the Cochrane review on oral morphine for cancerpain15 three studies with a total of 333 patients werereported comparing oral morphine with transdermalfentanyl.50–52 However, differences such as less
Radbruch et al. 589
Tab
le5.
Studie
sco
mpar
ing
rect
alw
ith
oth
er
applic
atio
nro
ute
s
stceffe edis :stluseR
yca ciffe : stlu seR
stn ei taP
Fir
st
auth
or,
year
Stu
dy
desi
gn
Pat
ient
num
bers
Ro
ute
Dru
gs
Out
com
em
easu
res
Sum
mar
y o
f res
ults
O
utco
me
mea
sure
s S
umm
ary
of r
esul
ts
Nar
rati
ve
sum
mar
y o
f res
ults
N
ote
s
Wiff
en
2007
Sy
stem
ic
revi
ew
5 st
udie
s (4
13
patie
nts)
Ora
l ver
sus
tran
sder
mal
(3
stu
dies
, 33
3 pa
tient
s),
oral
ver
sus
rect
al (
2 st
udie
s,
80 p
atie
nts)
Mor
phin
e,
fent
anyl
M
isce
llane
ous
Rec
tal f
aste
r on
set
and
long
er d
urat
ion
of p
ain
relie
f, tr
ansd
erm
al s
imila
r ef
ficac
y co
mpa
red
to o
ral
Mis
cella
neou
s T
rans
derm
al w
ith
less
con
stip
atio
n
Brue
ra
1995
C
ross
over
, ra
ndom
ized
tr
ial,
non-
blin
ded
23
Rec
tal v
ersu
ssc
Mor
phin
e V
AS
pain
in
tens
ity
(0-1
00),
VR
S (6
-ste
p,
from
McG
ill)
pain
inte
nsity
Mea
n V
AS
pain
inte
nsity
no
diff
eren
ce (
rect
al
13.2
, sub
cuta
neou
sly
13.3
), m
ean
VR
S m
inim
al
diffe
renc
e (r
ecta
l 0.7
, su
bcut
aneo
usly
0.9
, p
=0.
0459
)
VA
S na
usea
, se
datio
n (0
-100
)
VA
S se
datio
n no
di
ffere
nce
(rec
tal
23.2
, sub
cuta
neou
sly
24.5
), V
AS
naus
ea n
o di
ffere
nce
(rec
tal 7
.8,
subc
utan
eous
ly 9
.0)
Mea
n do
sage
326
±69
mg
(rec
tal)
and
138±
28 m
g (s
ubcu
tane
ous)
, 12
-hou
r in
terv
als
appr
opri
ate
with
rec
tal a
pplic
atio
n of
slo
w-
rele
ase
mor
phin
e, r
ecta
l ap
plic
atio
n is
a r
elia
ble,
no
ninv
asiv
e al
tern
ativ
e fo
r su
bcut
aneo
us a
pplic
atio
n
Mea
n co
nver
sion
ra
tion
rect
al:
subc
utan
eous
was
2.
4:1;
pow
er
anal
ysis
incl
uded
: 24
pat
ient
s 80
%
pow
er
Leow
19
95
Cas
e se
ries
12
iv
ver
sus
rect
ally
O
xyco
done
Pai
n in
tens
ity
VA
S
VA
S pr
e 5.
7±2.
0 /
4.7±
2.2(
iv/r
ecta
l); 3
0 m
in
0.4±
0.6
/ 2.4
±1.
8; 6
0 m
in
0.4±
1.2
/ 0.7
±0.
8; 1
20
min
1.3
±1.
8 / 0
.5±
0.5;
24
0 m
in 2
.0±
2.3
/ 0.
4±0.
4
VR
S 4-
step
for
drow
sine
ss,
light
head
edne
ss,
naus
ea,
vom
iting
, pr
uritu
s,
swea
ting
Dro
wsi
ness
and
lig
hthe
aded
ness
mos
t fr
eque
nt, n
ause
a m
ore
ofte
n w
ith
rect
al a
dmin
istr
atio
n
Both
rou
tes
prov
ided
sat
isfa
ctor
y an
alge
sia,
muc
h m
ore
rapi
d on
set
with
iv (
5-8
min
for
25%
pai
n re
duct
ion)
ver
sus
rect
al
(60-
120m
in)
Onl
y si
ngle
dos
e
590 Palliative Medicine 25(5)
Pann
uti
1982
C
ontr
olle
d co
hort
st
udy
102
Ora
l (37
), re
ctal
(37
), su
blin
gual
(28
)
Mor
phin
e Pa
in
inte
nsity
, 5-
step
VR
S fo
r ph
ysic
ian
ratin
g, V
AS
for
patie
nt
ratin
g
Ora
l rou
te (
11 w
eeks
fo
llow
-up)
: pai
n in
tens
ity
from
VA
S 7.
8 to
3.2
(p
<0.
01);
rect
al r
oute
(8
wee
ks fo
llow
-up)
: pai
n
inte
nsity
from
VA
S 9.
3 to
1.
3 (p
<0.
001)
; sub
lingu
al
rout
e (5
wee
ks fo
llow
-up
): pa
in in
tens
ity fr
om
VA
S 7.
8 to
2.7
(p<
0.00
1)
Perc
enta
ge o
f pa
tient
s C
onst
ipat
ion
(ora
l/rec
tal/s
ublin
gual
) 81
/89/
71%
of
patie
nts,
dro
wsi
ness
59/7
3/71
%, d
ry
mou
th 4
6/86
/61%
, vo
miti
ng 3
0/24
/18%
; dr
opou
t: or
al r
oute
2
patie
nts
beca
use
of
psyc
hosi
s, 3
vom
iting
, re
ctal
rou
te 2
pa
tient
s lo
cal
into
lera
nce
All
rout
es w
ere
effe
ctiv
e, a
utho
rsst
ate
mor
e ra
pid
and
sign
ifica
nt p
ain
rem
issi
on fo
r th
e su
blin
gual
rou
te,
alth
ough
rec
tal
was
sup
erio
r in
ph
ysic
ians
' as
sess
men
t
Brue
ra
1995
C
ontr
olle
d co
hort
st
udy,
non
-ra
ndom
ized
, op
en
37
All
patie
nts
pret
reat
men
t w
ith s
c,
chan
ge t
o or
al
(21
patie
nts)
ve
rsus
rec
tal
(16)
Hyd
rom
orp
hone
(p
retr
eat
men
t),
chan
ge t
o m
etha
done
VA
S pa
in
inte
nsity
(0
-100
)
VA
S pa
in in
tens
ity
redu
ced
from
50±
21
(pre
trea
tmen
t w
ith
hydr
omor
phon
e) t
o 29
±13
(re
ctal
m
etha
done
) an
d fr
om
51±
23 (
pret
reat
men
t w
ith h
ydro
mor
phon
e) t
o 39
±25
(or
al m
etha
done
). T
otal
cos
t 86
±12
8 C
anad
ian
fund
s (r
ecta
l) ve
rsus
228
±25
3 (o
ral),
m
uch
high
er w
ith s
c hy
drom
orph
one
pret
reat
men
t
Not
rep
orte
d M
ild s
edat
ion
and
cons
tipat
ion
in a
ll pa
tient
s, o
ther
sid
e ef
fect
s no
t re
port
ed
sepa
rate
ly fo
r re
ctal
ro
ute
Mea
n tim
e fo
r ch
ange
ove
r fr
om
pret
reat
men
t w
ith s
c 3.
2 ±3.
7 da
ys fo
r re
ctal
rou
te, 6
.5±
3.6
days
for
oral
. Slo
w s
witc
h to
m
etha
done
eith
er r
ecta
lly o
r or
ally
was
saf
e, e
ffect
ive
and
a lo
w c
ost
alte
rnat
ive
Con
vers
ion
fact
or
1.2±
1.3
for
sc
hydr
omor
phon
e/or
al m
etha
done
an
d 3±
2 fo
r sc
hy
drom
orph
one
to
rect
al m
etha
done
sc,
subcu
taneous;
iv,in
trav
enous;
VA
S,V
isual
Anal
ogu
eSc
ale;V
RS,
Verb
alR
atin
gSc
ale;N
RS,
Num
eri
calR
atin
gSc
ale.
Radbruch et al. 591
constipation and less sedation with transdermalfentanyl in one study and problems with managingthe change to fentanyl in another were attributed bythe authors more to the change of opioid than to thechange of route.
In the literature search seven studies with 310patients were found comparing transdermal withother alternative application routes (Table 6). Four ofthese studies compared transdermal with intravenousapplication and have been described in detail in thesection on intravenous application.40–43 Two otherscompared the transdermal with the subcutaneousroute and details are provided in the section on subcu-taneous application.17,35 In a retrospective chart evalu-ation, Ellershaw et al.36 matched pairs of patientsswitched from oral morphine to transdermal fentanylwith those switched to subcutaneous application ofdiamorphine and found little difference between thetwo groups.
The literature search identified another 13 studieswith a total of 801 patients treated with transdermalopioid application. Among these were three larger sur-veys using transdermal buprenorphine, which was partof the portfolio for the registration of the new trans-dermal therapeutic system.53–55 These studies demon-strated a significant higher number of responderscompared with placebo in a large number of patients,with a profile of adverse events that is similar toopioid application via other routes. Local symptomsat the application site were reported in several studies,with an incidence for erythema ranging from 3%(Likar et al.53) to 27.3% of patients (Sittl et al.55).One study with the buprenorphine patch reportedfewer local side effects with cancer patients comparedwith non-cancer patients.56 Pruritus at the patch sitewas reported with a similar incidence ranging from3.7% to 24.8% of patients. Other local side effectssuch as swelling or exanthema were reported onlyrarely.
In a recent study with cachectic patients57 the meandosage was significantly higher in cachectic patients(96� 29 mg/h) compared with normal weight(42� 10 mg/h), whereas plasma concentration were sig-nificantly lower in the cachectic patients. The authorsconcluded that absorption from the transdermal systemis impaired in cachectic patients.
Transmucosal or sublingual route
Opioid application via the oral, sublingual or nasalmucosa was compared with other routes in only onestudy. Pannuti et al.49 compared oral, rectal and sub-lingual morphine in a controlled study in 102 patients,and found a more rapid and more significant painremission with the sublingual application compared
with rectal or oral routes in the regression analysis ofpain behaviour.
The literature search identified another two studiesusing the transmucosal fentanyl application in39 patients58 or the sublingual application of fentanylin 10 patients,59 but both did not compare this withalternative routes.
Discussion
The literature search found a large number of studies,although only a few of those publications offered acomparison of different alternative routes for opioidtreatment. Even though morphine was predominantin these studies, a large number of opioids such ashydromorphone, oxycodone, methadone, fentanyl,buprenorphine, diamorphine, sufentanil or ketobemi-done were used. Intermittent injections, infusions withor without syringe pump devices were used for paren-teral application routes, and different solutions, tabletsor capsules with different pharmacokinetic propertieswere used for sublingual or rectal application.
No study used intramuscular injections in clinicalpractice. In only one case was intramuscular morphineadministered and the in description of the pharmacoki-netics properties of this route, it was reported as lesseffective as expected.49
The best evidence base was available for the subcu-taneous route with a systematic review and threerandomized controlled trials. A comparison of subcu-taneous and intravenous routes found no differences,confirming that both routes are feasible, effective andsafe. As the risk of complications is lower with subcu-taneous application, this route should be preferred.For patients with a port system or an indwellingvenous line for other therapeutic indications the intra-venous administration route would be an alternative.
Opioid administration with the rectal route wasinvestigated in four studies, one of which was a ran-domized controlled, crossover study. The publicationsdescribed comparable efficacy and safety with the par-enteral and rectal routes. Onset of analgesia wasdescribed as much faster following a single dose appli-cation of oxycodone intravenously in one study. On theother hand, rectal application seems to have a fasteronset than the oral application47 and the mean timeto change over from subcutaneous to rectal administra-tion took only half as long as the change over fromsubcutaneous to oral administration.
In spite of the wealth of research on transdermalopioid application, only seven studies comparing trans-dermal with other alternative routes were included inthis review. For the transdermal route it seems difficultto differentiate between effects of the opioid switch andthose of the route change. However, some studies
592 Palliative Medicine 25(5)
Tab
le6.
Studie
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tran
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sign
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nick
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le 4
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anyl
Kor
nick
20
03
See
Tab
le 4
9
Fent
anyl
Zec
h 19
92Se
e T
able
4
20
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ntan
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1997
Se
e T
able
4
50
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Wat
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98
See
Tab
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22
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anyl
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anyl
, su
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anyl
, hy
drom
orph
one
Elle
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w
2002
C
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olle
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tros
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eval
uatio
n
94
Tra
nsde
rmal
(47
pa
tient
s),
sc (
47)
Fent
anyl
(47
pa
tient
s),
diam
orph
ine
(47)
Pain
(co
ntro
lled/
un
cont
rolle
d)
Freq
uenc
y of
co
ntro
lled
pain
ob
serv
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ns d
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8 ho
urs
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ifica
ntly
hig
her
for
tran
sder
mal
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r 2/
12
obse
rvat
ion
peri
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her
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erio
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etro
spec
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, med
ian
dosa
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g,
diam
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ntro
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both
gro
ups
sc,
subcu
taneous.
Radbruch et al. 593
compared transdermal opioid therapy with subcutane-ous or intravenous administration of the same drug.This allows for a clear understanding that efficacyand tolerability are similar for both routes. More infor-mation on this will be provided in a separate systematicreview on transdermal treatment.
Transmucosal or sublingual application was investi-gated only rarely in comparison with other applicationroutes. Similarly, no reports at all were found for intra-nasal opioid application with the proposed search strat-egy. This is astonishing, as in recent years muchresearch on these application routes has been per-formed for the treatment of breakthrough pain withthe high number of new therapeutic systems that havebeen introduced in the last 2 years. However, these newsystems are indicated for breakthrough pain treatment,but not for treatment of continuous pain, and thus maynot be suitable alternative routes for patients not ableto use the oral route but requiring continuous aroundthe clock analgesia. Still, this lack of publicationspoints to a gap in the research agenda which has tobe addressed.
The new therapeutic systems have been compareddirectly against other alternative forms in a few studieson breakthrough pain, for example comparing intran-sasal fentenyl spray with transmucosal or intravenousapplication60,61 or reporting long-term efficacy.62
However, breakthrough pain will be considered in aseparate systematic review and so studies on break-through pain have not been considered in our review.
The side effect profile seemed to be very similar forthe subcutaneous, intravenous, rectal or transdermalroutes, with sedation, nausea, vomiting, dry mouthbeing most frequent as typical opioid-related sideeffects. Local side effects were reported for rectal appli-cation as well as for subcutaneous and transdermaladministration, with erythema and pruritus beingmost frequent.
Following the clinical experience of the experts, mostroutes seem to have clear indications, taking intoaccount their specific pharmacokinetic properties. Forexample, transdermal administration provides stableanalgesia, but reacts only sluggishly to dose changes,and this makes it suitable predominantly for patientswith chronic stable pain. Transmucosal fentanyl pro-vides a faster onset of analgesia, but is more fluctuantthan other administration forms.
This review included not only randomized controlledtrials but also non-randomized trials, and the low meth-odological quality of many of the studies included mayhave introduced bias. We did not assess potential biasacross the studies. The setting and the time frame forthe studies varied widely, and studies used a wide rangeof different outcome parameters on effectiveness as wellas on safety, thus preventing meaningful meta-analysis.
Randomized controlled trials with adequate size andmethodology comparing major alternative routes in ahead-to-head comparison are lacking.
Studies were retrieved only from Medline (PubMed)and only in English, and other publication databasesmight have added to the literature retrieved. Similarly,we did not contact authors or search handbooks.However, the consistency of the results clearly supportsthe conclusions from the review at least for subcutane-ous, intravenous, transdermal and rectal administrationroutes.
Conclusion
In conclusion, the systematic review found good evi-dence that subcutaneous administration of morphineor other opioids will be an effective alternative forcancer patients if oral treatment is not possible.
However, for a number of patients intravenous,rectal or transdermal therapy will offer a good alterna-tive to the subcutaneous route. The review found nosignificant differences in efficacy or side effects betweenthe alternative application routes.
Funding
The review is part of the work within the European PalliativeCare Research Collaboration (EPCRC). EPCRC is funded by
the European Commission’s Sixth Framework Programme(contract number LSHC-CT-2006-037777). Peter Trottenbergis funded as a research fellow by EPCRC.
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596 Palliative Medicine 25(5)
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