Appropriattezza ed inappropriatezza della

prescrizione di Analgesici

Federica AielliDipartimento 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 mgMaltoni 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 AEvan Seventer et al,2003, only about half patients completed the 4 week periodTawfik 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 opioid-naive 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 opioid-naive 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

Basse dosi Tapentadolo 6 2 1,7

Opioids: low doses in opioid-naive 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

A question of dosing…

The use of low doses of strong opioidsin naive patients.

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

All the three opioids used as first-line therapy:

were effective,

well tolerated,

required similar amounts of symptomatic drugs or co-analgesics.

Methadone was significantly less expensive, but required more changes, of the doses, suggesting that dose titration of this drug requires major clinical expertise.

“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

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

“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

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

WHO’s Pain Relief Ladder

FANS

Oppioidi deboli ±

adiuvanti

Oppioidi forti ±

adiuvanti

Oppioidi forti

Oppioidi forti +

adiuvanti

Rotazione

Tecniche Invasive

WHO’s Pain Relief Ladder: 2016