Paolo Marchettini
SUPSI, Manno Lugano
Ospedale San Raffaele, Milano
Le linee guida per il dolore neuropatico vanno
seguite?
No
 Clinical governance is a systematic approach to maintaining and


improving the quality of patient care within a health system.
Clinical governance became important in health care after the
Bristol heart scandal in 1995, during which anaesthetist Dr
Stephen Bolsin exposed the high mortality rate for paediatric
cardiac surgery at the Bristol Royal Infirmary. It was originally
elaborated within the United Kingdom National Health Service
(NHS), and its most widely cited formal definition describes it as:
A framework through which NHS organisations are accountable
for continually improving the quality of their services and
safeguarding high standards of care by creating an environment
in which excellence in clinical care will flourish.[1]
This definition is intended to embody three key attributes:
recognisably high standards of care, transparent responsibility
and accountability for those standards, and a constant dynamic of
improvement.
G. Scally and L. J. Donaldson,
Clinical governance and the drive for quality improvement in the new NHS in England BMJ (4 July 1998): 61-65
Clinical effectiveness: An approach to clinical trial design more relevant to
clinical practice, acknowledging the importance of individual differences
R.A. Moorea, S. Derrya,H.J. McQuaya, S. Straubeb, D. Aldingtona, P. Wiffenc, R.F. Belld, E. Kalsoe,
M.C. Rowbotham,for the ACTINPAIN writing group of the IASP Special Interest Group (SIG) on
Systematic Reviews in Pain Relief




Schwartz and Lellouch distinguished between explanatory trials (examining
whether an intervention works) and pragmatic trials (how best to use it in
clinical practice).
Clinical trials of new medicines are undertaken to satisfy the regulatory
requirements that drugs be efficacious and safe on average. Regulatory trials
are necessary, but not sufficient to answer many questions of practical
importance. Are antidepressants better than anticonvulsants in neuropathic
pain, and which antidepressant or anticonvulsant is best? Does failure to
respond to one drug preclude response to another drug, both within and across
classes?
We do not yet know how to predict efficacy in individual patients. To guide
treatment choice and care pathway development, determining what sequence
of interventions produces worthwhile benefit in the largest number in the
shortest time involves a different approach to clinically relevant outcomes.
Systematic reviews of regulatory trials often pool average data. In acute and
chronic pain, however, underlying distributions are commonly not normal,
tending to be U-shaped rather than bell-shaped, where the average
describes few individuals. Computations using such data can give the wrong
answer. Dichotomised responder analyses using a definition of “good”
response may be better in circumstances like these, and can be used to
calculate the numbers needed to treat and create league tables of efficacy and
useful treatment algorithms. However, guidelines and algorithms are
rarely tested to see how well they perform in practice.
“Managers and trialists may be happy for
treatments to work on average; patients expect
their doctors to do better than that”. In clinical
practice, if one treatment did not work for a
particular patient, another remedy was sought
until a satisfactory outcome was reached.
 Fewer than half with neuropathic pain achieve
adequate pain relief with any one therapy.
 A third of chronic pain patients discontinue opioids in
the short term, and up to half with musculoskeletal
pain discontinue NSAIDs in longer-term trials.
 Codeine has no analgesic effect in those unable to
metabolise it to morphine, works well in those who
can, while supermetabolisers pose problems.
 In migraine, only 24% achieved rapid and prolonged
pain relief without adverse events in one recent series
of studies of triptan therapy.
 Anti-TNF therapy gives substantial levels of benefit to
only 40% of patients with rheumatoid arthritis.
 For fibromyalgia and non-specific low back pain it is
recognised that oral medication treatments work in
only a small proportion of patients
Drei fiktive Studien A-C mit gleichem Ausgangschmerz,
alle drei gleiche mittlere Schmerzreduktion (p<0,001)
Sind die Studien vergleichbar ?
NRS vorher / nachher
10
40,09%
8
40,09%
50,01%
6
4
2
0
vor
nach
vor
Studie A
vor
Studie B
12
10
10
8
8
8
6
6
6
4
4
4
2
2
2
0
0
10
vorher
nacher
nach
Studie C
12
12
6
nach
0
vorher
nacher
vorher
nacher
© Maier 2012
7
Letteratura: CRPS dopo Dupytren: 6- 14 %
© Maier 2012
8
© Maier 2012
Generalizing from a controlled trial ?
C Williams et al. Pain 83 (1999)
Drop-out -Rate
rapporto abbandoni / partecipanti




10
inclusi 412 Pat.
abbandoni: 89 /
attesa eccessiva:
75 = 164 (40%)
Randomizzazione
respinta: 128
(31%)
incluso 121 (29%)
Christoph Maier
© Maier 2012
Recruitment report (NP 201781-504)
2500 Patients
• 1300 e-medical files
at our site
• 600 e-medica files at
medical office Bochum
• 600 paper files at pain
department Dortmund
700 Patients
appropriate diagnosis
100 Patients
inclusion/exclusion
criteria seem O.K.
no child-bearing
potential
adequate age (PZN)
2 Patients
100 Patients
inclusion/exclusion
criteria seem O.K.
Visit 1
no child-bearing
potential
adequate age (PZN)
Concomitant
disease (30%)
• thyroid gland
Patient
concern (15%)
Micellaneous
(15%)
• afraid of medication
• nerve root avulsion
• impaired kidney
• opioids WHO II
• work interference
• distance home - site
• vascular problems
• topical Lidocain
(especially PZN)
• time consumption
(same day / 11
weeks)
• psycological factors
• polyneuropathy
11
Concomitant
medication
(40%)
• anitdepressants ( TCA,
SNRI (e.g. Mirtrazapine)
Abteilung für Schmerztherapie Ltd. Arzt: Prof. Dr. med. Christoph Maier
Bürkle-de-la-Camp-Platz 1 D-44789 Bochum Mail: [email protected]
© Maier 2012
Effetti del trattamento nel tempo
10
Intensità del dolore
9
Placebo
8
Memantine
7
6
5
4
3
2
1
0
baseline (*)
1
12 Maier et al. Pain 103 (2003)
7
14
21
Durata dell’osservazione
28
© Maier 2012




Prozent
Prozent
Responder
ca. 3500 Paz. con Dolore da
artrosi, 7 RCT
Etoricoxib, Ibuprofene,
Celecoxib e Naprossene
Re-analisi del pool dei dati,
dropouts riportati come
mancato effetto
Responder
80
80
Verum (OA)
70
70
Verum
Placebo OA
Placebo
60
60
Verum (FM)
50
50
Placebo (FM)
40
40
30
30
20
20
Fibromyalgie (Häuser et al. Schmerz
2001)
10
10
00
00
13
2020
40
relief
PainPain
relief
40
60
60
80
80
© Maier 2012
10 mm
differenza
rispetto al
Placebo
>0,5 NNT
differenza
15
50 % di effetto
sostanziale
40 % solo
effetto minimo
1:2 probabilità di 1:5 rischio di
miglioramento > non aver alcun
50 %
miglioramento
© Maier 2012
MONTAS
Maier et al. Pain 97 (2002)
Intensità del dolore (NRS 0..10)
10
Morfina Placebo
8
6
4
Cross-over
2
Baseline
1. settimana
2. settimana
0
7
Durata del trattamento
14
0
16
© Maier 2012
 There are large interindividual differences in response to drug interventions in pain. For most



17
pain treatments, fewer than half of patients will have a good response, emphasising the
importance of judicious initial therapy choice, therapy sequences, and decision to change.
Traditional reporting of regulatory trials does not help us choose whom to treat with which
drug.
Lack of consensus on what constitutes a clinically useful change has not helped. The recent
IMMPACT deliberations have defined what constitutes minimal, moderate, and substantial
benefit. In osteoarthritis, and for some trials in neuropathic pain, we have results based on
these recommendations. Clinical effectiveness trials need to use outcomes of at least
moderate benefit, at least tolerable adverse events, and willingness to continue treatment.
Clinical effectiveness trials may have different structures, depending on whether the
population studied has a relatively straightforward disease or a complicated condition
(primary, secondary, or tertiary care). They will differ according to the intervention; well
understood oral therapy with adverse events that are common and reversible, or newer
invasive therapies where adverse events are more severe, irreversible, and not well
understood.
Clinical effectiveness trials may be difficult to organise, though perhaps not as expensive as
“classic” clinical trials done for regulatory purposes. Pharmaceutical companies may become
more interested in direct clinical efficacy trials as new methods of meta-analysis of existing
trials address drug choice for clinical practice . The academic community will probably have to
raise substantial sums and commit substantial personal resources to performing these trials,
though there is potential for innovative trials conducted internationally by using internet
recruiting and reporting. That will take time. While we wait, designing trials, and publishing
and discussing their merits and faults would be a good place to start.
© Maier 2012
Fig. 1 Practical consequences of different individual experiences of benefit and harm.
R.A. Moore , S. Derry , H.J. McQuay , S. Straube , D. Aldington , P. Wiffen , R.F. Bell , E. Kalso , M.C. Rowbo...
Clinical effectiveness: An approach to clinical trial design more relevant to clinical practice, acknowledging the importance
of individual differences
PAIN Volume 149, Issue 2 2010 173 - 176
http://dx.doi.org/10.1016/j.pain.2009.08.007
 In a simple example, if drug A has a greater analgesic effect but


more adverse event discontinuations than drug B, then drug B is
likely to be more clinically effective, because it generates pain
relief for more people for longer. Costs being equal, drug B would
be a sensible initial choice. Measurement of useful longer-term
outcomes would strengthen this conclusion and inform health
economic assessment.
An example of a clinical effectiveness study design might be used
to underpin care pathway development in chronic or recurrent
painful conditions by testing several drug/dose/titration options
chosen from randomised trial and meta-analytic evidence and
experience, especially when titration resulted in wide variations in
final effective dose and time to achieve it . Patients with
insufficient benefit or unacceptable adverse events proceed to
another drug or treatment, by physician choice, re-randomisation,
or according to a preset schedule, as appropriate.
The primary outcome is the proportion achieving a defined level
of pain relief with tolerable adverse events, measured for each
individual drug and overall for different treatment sequences
(A > B > C > D vs C > A > D > B, for instance).
Fig. 2 One possible clinical trial design for chronic or recurrent painful conditions. In this example, failures with drug A would move
to drugs B, C, or D after re-randomisation or physician choice; similar actions would apply to any other first...
R.A. Moore , S. Derry , H.J. McQuay , S. Straube , D. Aldington , P. Wiffen , R.F. Bell , E. Kalso , M.C. Rowbo...
Clinical effectiveness: An approach to clinical trial design more relevant to clinical practice, acknowledging the importance
of individual differences
PAIN Volume 149, Issue 2 2010 173 - 176
http://dx.doi.org/10.1016/j.pain.2009.08.007
Dolore neuropatico
A. Duloxetina
B. Pregabalina
C. Duloxetina + Pregabalina
D. Duloxetina + Pregabalina + Ossicodone
E se non funziona chiamate un medico
Prof g. Cruccu, Vienna, 15.11.2012
Sull’incertezza in Clinica
On peut avoir de l’incertitude, une vision négative : tâche
aveugle, handicap, boulet traîné par une médecine réduite à sa
dimension scientifique.
On peut aussi la voir, dans le cadre d’une clinique où l’humain
pondère la science, d’une manière positive : l’opportunité de
transformer l’incertitude du diagnostic, du traitement et du
pronostic en un espace pour ajuster et optimiser l’information du
malade conçue comme une parole qui soigne. C’est cette seconde
option qui est développée dans l’exposé écrit à partir d’une
conférence donnée à l’occasion d’un premier colloque sur « la
clinique de l’incertitude » organisé à Paris le 24 mars 2011
(Morel)
 la clinica è incerta
 La scienza è necessaria, ma insufficiente al clinico
 È necessario integrare l’incertezza nella scelta
terapeutica e riconoscere
 L’incertezza paralizzante
 L’incertezza occulta
 Come creare le condizioni per una valida decisione
clinica in situazioni di incertezza
 Bilanciare l’incertezza con certezze negative
 Definire i punti di incertezza per meglio contenerli
 Superare l’incertezza proiettandosi in una visione
futura
Evidence-based medicine is the conscientious,
explicit and judicious use of current best
evidence in making decisions about the care of
individual patients”. This emphasis on the
individual recognises that some patients will
have the ideal outcome of benefit without
adverse events, but others will have either no
benefit, or adverse events that are intolerable,
making continuation impossible even if they
do have benefit