Vol. 14 ?vb.

1July 1997 Journal of Pain and Symptom Management 15

Original Article

Opioid-Sparing Effect
of Diclofenac in Cancer Pain
S e b a s t i a n o M e r c a d a n t e , MD, M o n i c a Sapio, MD, M a r i n a Caligara, MD,
R o b e r t o Serretta, MD, Gabriella D a r d a n o n i , MD, a n d L u c a Barresi, MD
Department of Anesthesia and Intensive Care (S.M., M.S., R.S.), Buccheri La Ferla
Fatebenefratelli Hospital," Pain Relief and Palliative Care (S.M., L.B. ), S.A.M. O. T.;
Epidemiologic Observatory of Sicily (G.D.), Palermo," and Department of I~brensic Toxicology
(IVI.C.), University of Milan, Milan, Italy

Abstract
This study investigated the opioid-sparing effect of diclofenac using patient-controlled analgesia
with oral methadone. Fifteen patients with advanced cancer participated. After achieving
adequate analgesia with regnlar dosing of oral methadone (T1), patient-controlled analgesia
with methadone was administered for 3 days (T2). Intramuscular diclofenac 75 mg twice daily
was then added to this regimenfor 3 clays (T3). Compared to T2 values, methadone dose was
significantly reduced at T2 and T2, and pain report (recorded on a visual analogue scale)
was significantly reduced at T3. A reduction in methadone plasma concentration was also
observed at T2 and T3, although it did not attain statistical significance. Significant decreases
in the intensity of several symptoms other than pain were also found at T2 and T3. Diclofenac
appears to have a relevant opioid-sparing effect when using patio~t-controlled analgesia with
oral methadone. J Pain Sympotom Manage 1997;14:15-20. © U.S. Cancer Pain Relief
Committee, 1997.

~ywo~
Cancer pain; NSA1Ds, diclofenac; opioids, methadone; patient-controlled analgesia

Introduction variation of response in cancer patients and

T h e role of nonsteroidal anti-inflammatory
drugs (NSAIDs) in cancer pain has b e e n well
established in the t r e a t m e n t of mild pain and,
when c o m b i n e d with opioids in the t r e a t m e n t
of m o d e r a t e to severe pain. 1 NSAIDs have
b e e n shown to be effective in some specific
c a n c e r pain syndromes, such as m a l i g n a n t
b o n e pain, although there is a considerable
Address reprint requests to: Dr. Sebastiano Mercadante,
Pain Relief and Palliative Care, SAMOT, via Libert/t
191, 90143, Palermo, Italy.
Acceptedfor publication: October 18, 1996.
further investigation of efficacy is needed. 2'~ A
g o o d analgesic r e s p o n s e after a c o u r s e o f
NSAIDs has b e e n shown to have a positive pre-
dictive value for overall analgesic response in
cancer pain patients, regardless of the pain
mechanism. 4 Unlike opioids, the ceiling dose
limits the utility of the NSAIDs, and there is no
therapeutic gain in increasing dosages beyond
those r e c o m m e n d e d . Although NSAIDs may
provide additive analgesia w h e n c o m b i n e d
with opioids, there is no evidence that these
drugs truly p o t e n t i a t e opioid effects. 5 T h e
impact of NSAIDs in improving opioid analge-

Relief Committee, 1997

© U.S. C a n c e r Pain 0885-3924/97/$17.00
Published by Elsevier, New York, New York PII S0885-3924(97)00005-5
16 Mercadante et al. Vol. 14 No. 1July 1997

Table 1
Characteristics o f Patients and Previous Anticancer Trealments (Yes/No)
Age Gender Cancer P a i n (' Chem Surg Radi Horm

69 M Prostate 4 N Y Y Y
58 F Breast 2 3 34a Y Y Y N
65 M Head-neck 15 17 32b Y Y Y N
72 M Lung 36 N Y N N
63 M Pancreas 10 N Y N N
68 M Lung 11 N Y N N
61 F Ovarium 12b Y Y N N
63 M Lung 7 Y Y N N
69 F Liver 11 N N N N
72 F Breast 3 34a N Y Y Y
70 M Lung 7 34b N Y N N
62 M Lung 7 18b Y N N N
71 M Pancreas 10 N Y N N
64 F Colon 2 11 12a Y Y N N
70 F Uterus 14 N Y N Y
C h e m = c h e m o t h e r a p y ; surg = surgery; radi = radiation therapy; t m r m = h o r m o n e therapy.
" Pain syndromes: 2 = vertebral syndrome, 3 = long b o n e metastases, 4 = multiple metastases, 6 = pelvic
metastases, 7 = pleural disease, 10 = u p p e r a b d o m i n a l visceral involvement, 1 l = distension of hepatic
capsule, 1 2 a / 1 2 b = a b d o m i n a l or peritoneal disease w i t h o u t / w i t h chronic intestinal obstruction, 14
infiltration of p e r i n e u m , 15 = skin infiltration, 17 - h e a d - n e c k muscle infiltration, 18b - chest wall mass,
32b = skin d a m a g e from radiation therapy, 34 = postmastectomy syndrome, 34b = p o s t t h o r a c o t o m y
syndrome.

sia, t h e s p a r i n g effect, is difficult to study d u e r e g i m e n was s u s p e n d e d , a n d m e t h a d o n e was

to the s e q u e n c e o f t h e a n a l g e s i c l a d d e r p r o -
posed by the World Health Organization
( W H O ) , in w h i c h o p i o i d s a r e a d m i n i s t e r e d to
i m p r o v e a n a l g e s i a w h e n NSAIDs a l o n e a r e n o
l o n g e r effective. A c o m p a r i s o n b e t w e e n differ-
e n t g r o u p s t r e a t e d o r n o t with NSAIDs m a y
n o t b e useful d u e to the bias o f t h e i n t e r g r o u p
d i f f e r e n c e s a n d t h e D,pical i n d i v i d u a l r e s p o n s e
to analgesics in c a n c e r p a i n .
Patient-controlled analgesia c a n lye
e m p l o y e d to d e m o n s t r a t e t h e p o t e n c y o f anal-
gesic a g e n t s by m e a s u r i n g t h e o p i o i d - s p a r i n g
effect. ~5"-s T h e p u r p o s e o f this s t u d y was to
describe the opioid-sparing effect of
diclofenac, a common antiinflammatory drug,
u s i n g p a t i e n t - c o n t r o l l e d a n a l g e s i a with m e t h a -
done.
Methods
F i f t e e n a d v a n c e d c a n c e r p a t i e n t s were sur-
veyed. P a t i e n t c h a r a c t e r i s t i c s a r e p r e s e n t e d in
T a b l e 1. All p a t i e n t s h a d n o r m a l h e p a t i c a n d
r e n a l f u n c t i o n a n d were n o t receipting c h e m o -
t h e r a p y o r r a d i o t h e r a p y at t h e t i m e o f t h e
study. All p a t i e n t s w e r e e x a m i n e d a n d t r e a t e d
at h o m e o r at a n o u t p a t i e n t p a i n clinic. All
patients needed opioid therapy and had
a l r e a d y b e e n t r e a t e d with NSAIDs. P a i n syn-
d r o m e s w e r e r e c o r d e d a c c o r d i n g to c o d e s
u s e d at o u r i n s t i t u t i o n . T h e p r e v i o u s a n a l g e s i c
s t a r t e d at f i x e d h o u r s ( 3 - 5 m g o f m e t h a d o n e )
(TO) t h r e e times daily a c c o r d i n g to t h e age
( o v e r o r u n d e r 70 years, respectively) for 3
days or until adequate p a i n r e l i e f was
a c h i e v e d . Efforts w e r e m a d e to c o n t a c t t h e
p a t i e n t e v e r y day a n d c h a n g e t h e d o s a g e to
achieve a d e q u a t e p a i n r e l i e f with m i n i m a l dos-
age d u r i n g t h e s e 3 days (visual a n a l o g u e score
less t h a n 4, o r a p a i n level c o n s i d e r e d a c c e p t -
a b l e by t h e p a t i e n t ) . B e g i n n i n g at t i m e T1, t h e
s a m e d o s e u s e d to c o n t r o l p a i n was a d m i n i s -
t e r e d as n e e d e d . T h e p a t i e n t was t o l d to take
t h e d o s e i m m e d i a t e l y if the p a i n was b e c o m i n g
u n c o n t r o l l a b l e a n d to c o n t a c t t h e t e a m if p a i n
h a d n o t b e e n c o n t r o l l e d a f t e r two d o s e s .
P a t i e n t s were also a d v i s e d to take o n e d o s e
b e f o r e g o i n g to sleep, if n o d o s e h a d b e e n
a d m i n i s t e r e d in t h e last 8 hr. T h e p a t i e n t s
w e r e i n s t r u c t e d to r e p o r t t h e a m o u n t o f
m e t h a d o n e u s e d in t h e s u b s e q u e n t 3 days.
A f t e r 3 days, d i c l o f e n a c (75 rag) was s t a r t e d
i n t r a m u s c u l a r l y twice a day (T2), a n d p a t i e n t -
c o n t r o l l e d a n a l g e s i a with oral m e t h a d o n e was
c o n t i n u e d for a n o t h e r 3 days (T3). Laxatives
w e r e a d m i n i s t e r e d as s t a n d a r d t h e r a p y , a n d
a n t i e m e t i c s w e r e u s e d o n l y if s e v e r e gas-
trointestinal symptoms appeared. The study
d e s i g n is s h o w n in T a b l e 2.
S y m p t o m i n t e n s i t y [ s c o r e d as s l i g h t (1),
m o d e r a t e (2), o r severe (3)], m e t h a d o n e c o n -
s u m p t i o n , a n d visual a n a l o g u e scale (VAS)
Vol. 14 No. 1July 1997 Opioid-Sparing Effect of Diclofenac 17

Table 2
Study design
TO T1 T2 T3

M e t h a d o n e evaluation at fixed PC& with m e t h a d o n e d o s e d P(L~ with m e t h a d o n e Final

intervals to a d e q u a t e analgesia c o m b i n e d with diclofenac assessment
PCA, patient-controleld analgesia.

s c o r e f o r p a i n (0- to 10-cm scale) w e r e No influences of age or gender were

r e c o r d e d at T1, T2, and T3, globally consider-
ing the previous 3 days' t r e a t m e n t . Blood
samples for m e t h a d o n e analysis were drawn
f r o m ten patients at T1, T2, and T3 (at least 6
hr after the last m e t h a d o n e dose) and col-
lected into tubes containing heparin. After
centrifugation the plasma was separated and
stored frozen at - 2 0 ° C until analysis was per-
f o r m e d by gas c h r o m a t o g r a p h y c o m b i n e d with
mass spectrometry after liquid-liquid separa-
tion procedure. 9
Statistical analysis of the data was p e r f o r m e d
u s i n g analysis o f v a r i a n c e (ANOVA) f o r
r e p e a t e d m e a s u r e s for differences in doses
and concentrations of m e t h a d o n e , F r i e d m a n ' s
two-way ANOVA for n o n p a r a m e t r i c proce-
dures for VAS differences, a n d the Fisher's
exact a n d X2 tests for s y m p t o m s a n d their
trend. P e a r s o n ' s c o r r e l a t i o n coefficient was
used when required.
Resu/ts
No side effects related to diclofenac admin-
istration were r e p o r t e d during the study, and
no patient had p r o b l e m s in accepting the pro-
cedure of self-administering m e t h a d o n e . Anti-
emetics were n o t a d m i n i s t e r e d d u r i n g the
course of the study.
observed. A significant difference in metha-
d o n e c o n s u m p t i o n was observed between the
start of patient-controlled analgesia ~dth oral
m e t h a d o n e (T2) and the e n d of 3 days of
diclofenac t r e a t m e n t (T3) (P < 0.01) (Table
3). A significant decrease wa also r e p o r t e d in
VAS at T3 (P < 0.01). A reduction in metha-
d o n e plasma concentration was also observed
but did not reach significance probably due to
the low n u m b e r of plasma samples available.
No correlation was f o u n d between m e t h a d o n e
c o n s u m p t i o n and plasma concentration, due
to the large individual variation in m e t h a d o n e
plasma concentration. T h e r e was no variation
in effect by age or gender.
A significant decrease in the n u m b e r o f
patients with slight or m o d e r a t e confusion (P
< 0.05) a n d d r o w s i n e s s ( P < 0.01) was
observed at T2 and T3. Constipation signifi-
cantly increased at T2 and T3 when c o m p a r e d
with T1. A positive trend toward a reduction of
nausea and vomiting was also exddenced (P <
0.05), whereas no differences were observed
in dry mouth.
Discussion
In cancer patients, the use of NSAIDs may
delay the n e e d for opioid dose escalation or

Table 3
Data Recorded
T1 T2 T3

Methadone daily consumption (mg) 14.2 (2.6) 11.7 (3.4) 8.6 (3.4)**
Methadone concentration (ten patients, pg/mL) 135 (108) 112 (104) 83 (80l.
Pain (VAS) median (range) 3 (0-5) 3 (1-5) 2 (O-3)
S~nptom (intensity)
Nausea/vomiting (0/1-2) 6/9 10/5 12/3"
Confusion (0/1) 11/4 15/0 15/0"
Drowsiness (0/1-2) 0/15 10/5 13/2"£
Constipation (0/1-2) 13/2 1/14 2/13
Dry mouth (0/1-2) 4/11 4/11 5/10
Methadone daily constunption expressed as mean (standard deviation).
VAS, visual analogue scale score.
Symptom intensi~- (0 = absent, 1 = slight, 2 = moderate, and 3 - severe), and number of patients reporting symptoms.
Significance: **P < 0.01; *P < 0.05; methadone concentration and dry mouth not significant.
18 Mercadante et al.
allow the use of lower doses. This may result in
fewer central nervous system side effects. If
toxicity, does not occur f r o m NSAID adminis-
tration, the reduction in adverse effects may
improve patient function and the quality of
residual life. NSAIDs may have activity that
extends beyond their accepted peripheral
analgesic effect; they e x e r t s o m e o f t h e i r
e f f e c t s o n t h e c e n t r a l n e r v o u s system. 1°
NSAIDs have b e e n r e p o r t e d to have a specific
effect in relieving malignant b o n e pain, ll but
the question of specific efficacy of n o n o p i o i d
analgesics in m a l i g n a n t b o n e pain has not
b e e n addressed appropriately, as no studies
have e x a m i n e d their effects in c o m p a r i s o n
with n o n m a l i g n a n t b o n e p a i n 3 M a l i g n a n t
nerve pain was m o r e responsive to 1500 m g of
n a p r o x e n than to 60 m g of slow-release mor-
phine, lz
Diclofenac is increasingly used a l o n e or
c o m b i n e d with opioids in the t r e a t m e n t of
cancer pain. 13-15 In one study, 16 diclofenac
had a m o r p h i n e - s p a r i n g effect of 14%, and
provided better s)~nptom control when a d d e d
to continuous, parenteral, patient-controlled
administration of m o r p h i n e in patients with
severe cancer pain.
In a pre~fious evaluation of 4 years' experi-
ence, 17 the duration of the W H O first step
therapy for cancer pain (nonopioid analgesics
alone) ranged between 19 and 42 days; this
period of good pain relief o c c u r r e d during an
observation period (referral until death) of
37-61 days. Therefore, a b o u t one-half of the
analgesic therapy period could be covered by
n o n o p i o i d s . L o n g - t e r m a d m i n i s t r a t i o n of
NSAIDs a l o n e or c o m b i n e d with o p i o i d s
( m o r e than 6 m o n t h s or until death) has also
b e e n r e p o r t e d in several patients without side
effects specifically attributable to the use of
NSAIDs. is The average length of t r e a t m e n t for
NSAIDs administered alone was 19.5 days, and
the m e a n pain relief on a VAS pain scale went
f r o m 54 m m to 23 m m (approximately 50% of
r e d u c t i o n ) after 4 days of NSAID therapy.
Opioid administration was motivated in only
52% of cases by the ineffectiveness of analge-
sia. Moreover, the combination of these drugs
with opioids remarkably e n h a n c e d their anal-
gesic effect. Similar results have been
observed by others.
M e t h a d o n e ' s analgesic potential for cancer
p a i n c o n t r o l has l o n g b e e n r e c o g n i z e d , a9
Vol. 14 No. l July 1997
M e t h a d o n e seemed suitable for this study, as it
has an acceptable onset and a lasting effect,
which may improve the patient's compliance.
T h e initiation of m e t h a d o n e therapy on an
as-needed basis is often r e c o m m e n d e d for safe
d e t e r m i n a t i o n of the duration of analgesia in
an individual patient. 2°'zl A flexible fixed dose
of m e t h a d o n e at patient-controlled intervals
may be useful for the individualization of anal-
gesic dosage and, therefore, the optimization
of pain m a n a g e m e n t in cancer pain patients.
In this study, a s i g n i f i c a n t d e c r e a s e in
m e t h a d o n e c o n s u m p t i o n was observed when
switching f r o m r e g u l a r d o s i n g to p a t i e n t -
controlled analgesia. A further reduction on
m e t h a d o n e r e q u i r e m e n t was o b t a i n e d after
the a d m i n i s t r a t i o n o f diclofenac. Although
m e t h a d o n e ' s pharmacokinetics could explain
the reduced doses at T2, it is unlikely to have
an effect when the patient was controlling the
dose to achieve acceptable analgesia. A rel-
evant decrease in m e t h a d o n e c o n s u m p t i o n ,
a s s o c i a t e d with a b e t t e r p a i n VAS, was
observed after administering diclofenac.
Methadone plasma concentration also
decreased, although it did not reach statistical
significance. As expected, substantial interindi-
vidual variation in the relationship between
changes in plasma m e t h a d o n e concentration
and analgesia in patients with chronic pain
receiving m e t h a d o n e was observed. 22
Although the maximal effect of NSAIDs usu-
ally takes several weeks in the t r e a t m e n t of
arthropathy, the m a x i m a l effect on c a n c e r
pain usually can be m e a s u r e d after j u s t a
c o u p l e o f days. z3 O b s e r v a t i o n g u i d e d the
selection of the interval chosen to identify the
expected maximal effect. A placebo effect or
carryover effect c a n n o t be ruled out but is
unlikely given that methadone doses
d e c r e a s e d after starting diclofenac b u t n o t
a f t e r s t a r t i n g p a t i e n t - c o n t r o l l e d analgesic
(between T1 and T2). Although a two-way
crossover comparison or a two-arm controlled
study would better address these concerns,
these study designs might be influenced by an
alteration of the pain syndrome and its inten-
sity during m o r e p r o l o n g e d periods of study
or by the large interindividual variation of the
analgesic response to b o t h m e t h a d o n e and
diclofenac. The treatment period chosen
appears to be long e n o u g h to a p p r o a c h maxi-
Vol. 14 No. 1 July 1997 Opioid-Sparing Effect of Diclofenac
mal response and limit the incidence of drop-
outs or spontaneous change of disease.
In this study, b l o o d levels of m e t h a d o n e
were determined once patients achieved stable
pain. If an opioid-sparing effect with similar or
i m p r o v e d s y m p t o m c o n t r o l o c c u r r e d after
administration of drug B in the presence of
u n c h a n g e d or decreased blood level of drug
A, it can be assumed that there is a genuine
analgesic potentiating effect, rather than a
change in effect due to increased bioavailabil-
ity o f d r u g s , z4 However, this t h e o r e t i c a l
assumption may be difficult to demonstrate in
the case of m e t h a d o n e , because of its pharma-
cokinetic characteristics. Nonetheless,
diclofenac has been shown not to modi~' mor-
phine pharmacokinetics in cancer patients, 1~
and these observations, taken together, sup-
port the evidence that diclofenac exerts its
analgesic effect independently of any modifi-
cation of the opioid.
A reduction of symptoms c o m m o n l y associ-
ated with opioid therapy, except constipation,
was observed. However, this could be attrib-
uted to the o c c u r r e n c e of tolerance during
the study. There was no relationship between
plasma m e t h a d o n e level and symptoms. This
finding duplicates a study of patients in a
m e t h a d o n e m a i n t e n a n c e p r o g r a m . 2~ This
observation probably indicates that metha-
done in the biophase at receptor sites is not in
rapid reversible equilibrium with m e t h a d o n e
in the ambient tissue water. It follows that
m e t h a d o n e plasma levels do not accurately
reflect the effective concentrations of metha-
done at the receptor sites. As a consequence,
varying d o s i n g regimens, such as patient-
controlled analgesia, may be a useful guide for
the administration of m e t h a d o n e in cancer
pain patients. 26
Morphine was not indicated as a test drug in
this study because of the relatively short dura-
tion o f e f f e c t t h a t m a k e s its use o n an
as-needed basis difficult and may limit patient
compliance. Slow-release formulations were
also unsuitable for the purpose of the study. In
a pre~4ous study, t6 it was difficult to maintain
patients because of problems with accepting
the p r o c e d u r e of self-administering intrave-
nous morphine.
The value of an opioid-sparing effect may be
questioned in cancer pain treatment. By itself,
the ability to limit opioid dosing should not
19
merely be an indication to add NSAIDs to an
opioid regimen, as the same level of analgesia
can be achieved by increasing opioid dose. It
must be recognized that the addition of an
NSAID to a t h e r a p e u t i c r e g i m e n exposes
patients to the side effects of another medica-
tion. 27 However, the use of NSMDs may be
useful when the increases in opioid dosage
cause opioid toxicity, as they provide additive
analgesia when c o m b i n e d with opioid drugs
and can reduce the need for dose escalation.
They may be particularly valuable in patients
with grossly inflammatory lesions. 2~ Moreover,
their use is currently suggested by the W H O
guidelines on cancer pain treatment.
In conclusion, diclofenac sodium appears to
have a relevant opioid-sparing effect in cancer
pain when using the model presented in this
study, that is patient-controlled analgesia by
oral m e t h a d o n e . C a u t i o n s h o u l d be used
when using NSAIDs for p r o l o n g e d periods.
Long-term studies with NSMDs in cancer pain
are lacking.
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