Paolo MarchettiniSUPSI, 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

© Maier 20126

vor nach vor nach vor nachStudie A Studie B Studie C

0

2

4

6

8

10

NRS vorher / nachher

Drei fiktive Studien A-C mit gleichem Ausgangschmerz, alle drei gleiche mittlere Schmerzreduktion (p<0,001)

Sind die Studien vergleichbar ?

vorher nacher0

2

4

6

8

10

12

vorher nacher0

2

4

6

8

10

12

vorher nacher0

2

4

6

8

10

12

40,09% 40,09% 50,01%

© Maier 20127 Letteratura: CRPS dopo Dupytren: 6- 14 %

© Maier 20128

© Maier 201210

Generalizing from a controlled trial ?C Williams et al. Pain 83 (1999)

Drop-out -Rate rapporto abbandoni / partecipanti

inclusi 412 Pat. abbandoni: 89 /

attesa eccessiva: 75 = 164 (40%)

Randomizzazione respinta: 128 (31%)

incluso 121 (29%)

Christoph Maier

© Maier 201211

Recruitment report (NP 201781-504)

2 Patients

Visit 1

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 Patientsinclusion/exclusion criteria seem O.K.

no child-bearing potential

adequate age (PZN)

Abteilung für Schmerztherapie Ltd. Arzt: Prof. Dr. med. Christoph MaierBürkle-de-la-Camp-Platz 1 D-44789 Bochum Mail: christoph.maier@ruhr-uni-bochum.de

100 Patientsinclusion/exclusion criteria seem O.K.

no child-bearing potential

adequate age (PZN)

Concomitant disease (30%)

• thyroid gland

• impaired kidney

• vascular problems

• polyneuropathy

Patient concern (15%)• afraid of medication

• work interference

• time consumption (same day / 11 weeks)

Micellaneous (15%)

• nerve root avulsion

• distance home - site

• psycological factors

Concomitant medication

(40%)• opioids WHO II

• topical Lidocain (especially PZN)

• anitdepressants ( TCA, SNRI (e.g. Mirtrazapine)

© Maier 201212

Inte

ns

ità

de

l do

lore

0

1

2

3

4

5

6

7

8

9

10

baseline (*)1 2821147

Durata dell’osservazione

Placebo Memantine

Effetti del trattamento nel tempo

Maier et al. Pain 103 (2003)

© Maier 201213

10 20 30 40 50 60 70 800

10

20

30

40

50

60

70

80

Verum Placebo

Pain relief

Prozent Respond

er 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

10 20 30 40 50 60 70 800

10

20

30

40

50

60

70

80Verum (OA)

Placebo OA

Verum (FM)

Placebo (FM)

Pain relief

Prozent Responder

Fibromyalgie (Häuser et al. Schmerz 2001)

© Maier 201215

10 mm differenza rispetto al Placebo

50 % di effetto sostanziale

40 % solo effetto minimo

>0,5 NNT differenza

1:2 probabilità di miglioramento > 50 %

1:5 rischio di non aver alcun miglioramento

© Maier 201216

Intensità del dolore (NRS 0..10)

Durata del trattamento0 7 14

0

2

4

6

8

10

Baseline 1. settimana 2. settimana

Morfina Placebo

MONTAS

Cross-over

Maier et al. Pain 97 (2002)

© Maier 201217

There are large interindividual differences in response to drug interventions in pain. For most 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.

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 neuropaticoA. Duloxetina B. PregabalinaC. Duloxetina + PregabalinaD. Duloxetina + Pregabalina + Ossicodone

E se non funziona chiamate un medico

Prof g. Cruccu, Vienna, 15.11.2012

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)

Sull’incertezza in Clinica

la clinica è incerta La scienza è necessaria, ma insufficiente al clinicoÈ necessario integrare l’incertezza nella scelta

terapeutica e riconoscereL’incertezza paralizzanteL’incertezza occultaCome creare le condizioni per una valida decisione

clinica in situazioni di incertezzaBilanciare l’incertezza con certezze negativeDefinire i punti di incertezza per meglio contenerliSuperare 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