Transcript Opioids - Cipomo

Appropriattezza ed
inappropriatezza della
prescrizione di Analgesici
Federica Aielli
Dipartimento di Scienze Cliniche Appllicate e Biotecnologiche
Università degli Studi dell’Aquila
Treatment of cancer pain
WHO’s Pain Relief Ladder
ESMO Clinical Practice
Guidelines 2012
WHO Step II opioids
 Mild-moderate pain:
Weak opioids:
Codeine
Tramadol
Rodriguez RF, et al. J Palliat Med
2007:
 no difference in efficacy
between tramadol, codeine
plus paracetamol, and
hydrocodone plus paracetamol
 tramadol was associated with
more side-effects
Tassinari D, et al. Palliat Med 2011:
 Codeina and tramadol are
effecive compared with
placebo
Is codeine some morphine?
 0-15% of codeine is demethylated to morphine
by CYP2D6 (high genetic polymorphism)
 7-10% are poor metabolizers….
 Poor metabolizers had no analgesia with
codeine
(Sintrup, 1993, Poulsen, 1996)
Wilder-Smith CH, et al. Oral tramadol, a μ-opioid
agonist and monoamine reuptake-blocker, and
morphine for strong cancer-related pain. Ann Oncol 1994

The mean pain intensity was similar with morphine and with
tramadol

The total number of side-effects per person was lower on
the fourth day with tramadol (p < 0.05),

the severity of nausea (p < 0.05) and constipation
decreased with tramadol (p < 0.05).

Three patients dropped out of the morphine group due to
side-effects and 4 out of the tramadol group due to
inadequate analgesia.
Wilder-Smith CH, et al. Oral tramadol, a μ-opioid
agonist and monoamine reuptake-blocker, and
morphine for strong cancer-related pain. Ann Oncol
1994

Rated pain control better with morphine (p <
0.03), but the tolerability of tramadol was judged
superior (p < 0.002).
mean daily doses on day 4 were
101 +/- 58 mg of morphine
The use of strong opioids, particularly with TTS fentanyl, in opioid
naive patients to by-pass the second step drugs.
Critical point: opioid starting doses
Mistakidou 2002, 0.6 mg fentanyl,
Marinangeli, 2004, unknown, presumably morphine equivalent 60 mg
Maltoni 2005, morphine equivalent 60 mg
According to this information it should be assumed that doses of 0.6 mg/day of TTS
fentanyl or equivalent doses of 60 mg/day of oral morphine, can be safety used in
opioid-naive pts.
Vilkmayer 1999, 0.6 mg fentanyl, more AE
van Seventer et al,2003, only about half patients completed the 4 week period
Tawfik et al,2004, opioid-naive patients receiving 0.6 mg/die of TTS fentanyl developed
relevant AE in comparison with tolerant pts and were more likely to withdrew because of
AE
What is the tolerated starting dose in opioid naive pts having moderate pain?
Doses of about 60 mg/day in naive-patients are likely to produce drop-out due to AE
Opioids: low doses in opioid-naive
patients

Mercadante S, Porzio G, Ferrera P et al “Low morphine
doses in opioid-naive cancer patients with pain.” J Pain
Symptom Manage 2006 Mar;31(3):242-7.

Mercadante S, Porzio G, Ferrera P et al “Low doses of
transdermal buprenorphine in opioid-naive patients with
cancer pain: a 4-week, nonrandomized, open-label,
uncontrolled observational study.” Clin Ther 2009 Oct;
31(10):2134-8
Opioids: low doses in opioid-naive
patients

Mercadante S, Porzio G, Ferrera P et al “Low doses of
transdermal fentanyl in opioid naive patients with cancer
pain” Curr Med Res Opin. 2010 Dec;26(12):2765-8

Mercadante S, Porzio G, Ferrera P, Aielli F, Adile C, Ficorella
C, Giarratano A, Casuccio A. Tapentadol in cancer pain
management: a prospective open-label study. Curr Med
Res Opin. 2012 Nov;28(11):1775-9
Opioids: low doses in opioidnaive patients
N°
pazienti
Dose T0
Dose T4
Basse dosi morfina
102
15 mg
45 mg
Basse dosi
buprenorfina
31
0,3 mg
0,67 mg
Basse dosi Fentanyl
39
0,4 mg
0,8 mg
Basse dosi
Tapentadolo
50
100 mg
200 mg
Opioids: low doses in opioidnaive patients
Pain Intensity T0
Pain Intensity T4
giorni
Basse dosi morfina
6,1
3
2
Basse dosi
buprenorfina
6,4
3
1,5
Basse dosi Fentanyl
6,4
3,2
1,7
6
2
1,7
Basse dosi
Tapentadolo
Opioids: low doses in opioidnaive patients
T0
T1
T4
Nausea/vomito
0,1-0,8
0,2-0,9
0,1-0,8
Stipsi
0,4-0,5
0,4-0,9
1,2-1,8
Sonnolenza
0,1-0,3
0,6-0,8
0,5-0,7
Confusione
0,1-0,4
0,2-0,5
0,2-0,4
Scala da 0 a 3
The use of low doses of strong opioids
in naive patients.
A question of dosing…
Management of cancer pain:
ESMO Clinical Recommendations 2012

Weak opioids such as codeine, tramadol and
dihydrocodeine should be given in combination
with non-opioid analgesicsAs [III, C]

An alternative to weak opioids, consider low doses
of strong opiods in combination with non-opioid
analgesics. [III, C]
The role of the second step of the
WHO analgesic ladder is still open!
WHO Step III opioid first
choice

Morphine is the prototype opioid analgesic, and
for 25 years oral morphine has been deemed the
drug of first choice for treating moderate to
severe cancer pain.

Novel formulations of old opioids, such as
oxycodone, hydromorphone, Buprenorphine
and fentanyl and new opioids such as
tapendadol have been developed and the
availability of different opioids across the world
has improved.
WHO Step III opioid first
choice

Morphine has remained the first choice for
reasons of familiarity, availability, and cost rather
than proven superiority.

The data show no important differences
between morphine, oxycodone, and
hydromorphone given by the oral route and
permit a weak recommendation that any one of
these three drugs can be used as the first choice
step III opioid for moderate to severe cancer
pain
“Sustained-release oral morphine versus
transdermal fentanyl and oral methadone in
cancer pain management.”
Mercadante S, Porzio G, Ferrera P, et al. Eur J Pain. 2008


All the three opioids used as first-line therapy:

were effective,

well tolerated,

required similar amounts of symptomatic drugs or coanalgesics.
Methadone was significantly less expensive, but
required more changes, of the doses, suggesting that
dose titration of this drug requires major clinical
expertise.
“Switching from Transdermal Drugs: An
Observational ‘‘N of 1’’ Study of Fentanyl and
Buprenorphine”
Mercadante S, Porzio G, et al. J Pain Symptom Manage 2007

No statistical differences in changes in pain and
symptom intensity.

No significant changes in rescue doses of oral
morphine were reported at the same intervals.

Cancer patients receiving stable doses of TTS FE or TTS
BU can be safely switched to the alternative
transdermal opioid
Role of paracetamol and
NSAIDs
The role of paracetamol and nonsteroidal anti-inflammatory
drugs in addition to WHO Step III opioids in the control of
pain in advanced cancer. A systematic review of the
literature. Nabal M, et al. Pall Med 2012

The evidence from the available clinical trials is of
limited amount and quality, but it weakly supports the
proposal that the addition of an NSAIDs to WHO Step
III opioids can improve analgesia or reduce opioid
dose requirement.

There is insufficient evidence to support the use of
paracetamol in combination with Step III opioids.

Data on the toxicity of NSAIDs in this indication are
insufficient owing to the small number of patients and
the short duration of treatment reported in the
studies.
Nonopioid drugs in the treatment of
cancer pain. Vardy J, Agar M, J Clin Oncol
2014

Most of the acetaminophen and NSAID studies in
patients with cancer had small sample sizes and were
of short duration, and none included selective COX-2
inhibitors.

Longer term efficacy and safety remain unknown,
with prevalence and severity of toxicities not
quantified in patients with cancer.

Studies have not been adequately powered to
determine whether NSAIDs or acetaminophen are
more beneficial for certain types of cancer pain,
although anecdotally, it is suggested that NSAIDs are
more effective for pain associated with inflammation
Role of paracetamol and
NSAIDs in addition to opioids

ESMO Clinical Practice guideline:


no information
EAPC evidence-based recommendations:

weak recommendation to add NSAIDs to step III
opioids to improve analgesia or reduce the opioid
dose required to achieve analgesia.
Neuropathic pain:
 Tricyclic antidepressants
(amitriptyline, imipramine)
 Antiepilectics (gabapentin,
pregabalin)
ESMO Clinical Practice guideline:
 Patients with NP should be
treated with non opioid and
opioid drugs [III, B].
 Patients with NP should be
given either a tricyclic
antidepressant or a
anticonvulsant and subjected
to side effects monitoring [I, A].
EAPC evidence-based
recommendations:
strong recommendation that amitriptyline or
gabapentin should be considered for patients with
neuropathic cancer pain that is only partially
responsive to opioid analgesia
Mercadante S, et al. The effects of low doses of pregabalin
on morphine analgesia in advanced cancer patients. Clin J
Pain. 2013 Jan;29(1):15-9
 48 patients completed
the study, 30 and 18
patients in groups MO
and MO-PR, respectively
 No statistical differences
were observed.
 No differences were found
in quality of life and all BPI
items
 10 patients had a definite
neuropathic pain; as
expected, this did not
indicate a significant
difference
Bennett MI, et al. Pregabalin for the management of
neuropathic pain in adults with cancer: a systematic review
of the literature. Pain Med. 2013 Nov;14(11):1681-8
 The studies included one
double-blind randomized
controlled trial, one single-arm
open-label study, two
observational analyses, and
one case report
 Not possible to draw any
conclusions on the
descriptive summary of
pregabalin for the
treatment of cancer
related neuropathic pain
Adjuvant drugs?

only selected patients (highly responsive)

the drugs should not be initiated at once

” add on” strategy
Ladder:
WHO’s Pain Relief Ladder
2016
Tecniche
Invasive
Oppioidi
Rotazione
forti ±
adiuvanti
Oppioidi forti
+ adiuvanti
Oppioidi
deboli
±
Oppioidi
adiuvanti
forti
FANS