Dolore cronico e depressione

Giovanni Gambassi

Disclosure

• Honoraria for participation to advisory boards

• Educational grants

- Grunenthal

- Mundipharma

- Molteni

The chicken and the egg

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

Emotional component

Sensory

component

Integrative/discriminatory

component

My brain is hurting me

Emotional, motivational, affect

Sensory coding

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

PAIN An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage

IASP, Subcommittee on Taxonomy, 1979

Aug. 15, 1997;277:968-71

Pain affect encoded in human anterior cingulate cortex

PET scans of pain-related activity associated with suggestions of high and low unpleasantness

Neuronal activation in anterior cingulate cortex are necessary for the perception of pain-related unpleasantness.

July 3, 2001 98(14):8077-82

Un dolore provocato dal medesimo stimolo nocivo evoca

attivazione cerebrale (PET misurata) di intensità diversa a

secondo della piacevolezza percepita nella relazione

Science 20 February 2004:

Vol. 303. no. 5661, pp. 1157 - 1162

Le aree cerebrali che si

attivano quando ci viene

imposto uno stimolo

nocivo sul nostro corpo

sono le stesse che si attivano quando “viviamo

e sentiamo” il dolore

di persone con cui siamo

in relazione emotiva-

affettiva

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

0

20

40

60

80

100

CZ D DK F FIN I IS NL NO S UK Total

Pre

vale

nce

of

pain

(%)

Gambassi et al.

AdHOC J Gerontol – Med Sci 2008

SHELTER-pilot

0

5

10

15

20

25

30

Community Primary CareClinic

MedicalInpatientSetting

NursingHome

Prevalence

of Major

Depression

(%)

Katon W, Schulberg H. Gen Hosp Psychiatry. 1992;14:237-247.

Rosen J, Mulsant BH, Pollock BG. Nursing Home Med. 1997;5:156-165.

2%–4%

5%–10%

6%–25%

6%–14%

Major Depression Is Associated with Chronic Medical Illness

Association Between Pain and Depression

Method: We conducted a cross-sectional study using data from the Aged in Home

Care (AdHOC) database. Pain was defined as any type of pain manifested over the 7 days preceding the assessment. Depression was defined as a score > = 3 on

the Minimum Data Set Depression Rating Scale.

Results: Mean age of 3976 subjects entering the study was 82.3 years, and 2948 (74.1%) were women. Of the total sample, 2380 subjects presented with pain

(59.9%), depression was diagnosed in 181 (11.3%) of the 1596 participants without pain and in 464 (19.5%) of the 2380 participants with pain (p < .001).

After adjusting for potential confounders, pain was significantly associated with depression (odds ratio [OR] 1.76, 95% confidence interval [CI] = 1.43 to 2.17).

Gambassi et al. J Clin Psychiatry 2005;66:982-8

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

Increased affective processing even before actually experiencing pain

For the same intensity of painful stimulation, subjects with depression show

maladaptive activation of a neural network involved in pain and emotion modulation

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

Patients With Pain Show Gray-Matter Loss in Pain-Processing Structures

Volu

me 7

1(1

), J

an

uary

2009,

pp

49-5

6

Patients With Pain Show Gray-Matter Loss in Pain-Processing Structures

Central-supraspinal sensitization

Chronic pain may be a reflection of decreased sensory processing and

enhanced emotional/cognitive processing.

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

PAIN DEPRESSION

Depression leads

to chronic pain Two independent but

related processes

Chronic pain leads

to depression

PAIN DEPRESSION

Outline

• Una nuova idea del dolore

• Una nuova clinica del dolore

• Dolore e depressione

• Depressione conduce al dolore

• Dolore porta alla depressione

• Visione moderna

• Trattamento

Paradoxical paucity of data (>short-term);

heterogeneity, poor quality, in general, big

placebo effect

JAGS 2002;50:1962-8

Gambassi et al.

Integrated Primary Care Information (IPCI) database

66%

DPN

Antidepressants for neuropathic pain

T Saarto, PJ Wiffen

Cochrane Database of Systematic Reviews 2008 Issue 2

This update has provided additional confirmation on the effectiveness of

antidepressants for neuropathic pain and has provided new information on another

antidepressant - venlafaxine. There is still limited evidence for the role of SSRIs.

Whether antidepressants prevent the development of neuropathic pain (pre-

emptive use) is still unclear. Both TCAs and venlafaxine have NNTs of approximately three. This means that for approximately every three patients with

neuropathic pain who are treated with either of these antidepressants, one will get

at least moderate pain relief. There is evidence to suggest that other

antidepressants may be effective but numbers of participants are insufficient

to calculate robust NNTs. SSRIs are generally better tolerated by patients and more high quality studies are required.

SAGE

Vince me

Constantine

Kate

Systematic Assessment of Geriatric drug use via Epidemiology

Gambassi et al.

J Am Geriatr Soc 1998;26:250-2

Med Care 1998;36:167-79

Am J Pharm 1998;13:1356-64

J Gerontol 1999;54A:M25-33

Can J Aging 2000;19:67-86

More than a single drug may be necessary. Moreover, a

combination of two or more drugs with complementary

mechanisms of action may work synergistically to afford

greater relief with less toxicity.

Tramadol for neuropathic pain

Cochrane Database of Systematic Reviews 2008 Issue 4

We identified six eligible trials

four comparing tramadol with placebo,

one comparing tramadol with clomipramine,

one comparing tramadol with morphine.

All four trials comparing tramadol with placebo showed a significant

reduction in neuropathic pain with tramadol.

Three of the trials which compared tramadol to placebo (total 269

participants) were combined in a meta-analysis. The number needed to

treat with tramadol compared to placebo to reach at least 50% pain relief

was 3.8 (95% confidence interval 2.8 to 6.3).

There were insufficient data to draw conclusions about the effectiveness

of tramadol compared to either clomipramine or morphine.

Meccanismo d�azione di tapentadolo

(attività MOR + attività NRI) (livello spinale)

MOR(agonista del recettore µ dell�oppioide)

NRINRI(Inibitore del reuptake della noradrenalina)

Segnaledoloroso

Via discendentenoradrenergica

Segnale di dolore

Via ascendenteTAP TAP

L�attività complementare e sinergica MOR-NRI Riduzione della trasmissione ascendente + Potenziamento dell�inibizione discendente

References: Tzschentke TM. et al. Drugs of Today 2009, 45 (7): 483-496

Sviluppo clinico di tapentadolo

►Oltre 5000 pazienti (studi di fase II/III)

►Dolore cronico da moderato a grave (>80% grave)

►Principali studi di fase III sul dolore cronico:

Randomizati, in doppio cieco, controllati vs placebo e confronto attivo

Lombalgia (LBP) N= 981

Artrosi (OA, ginocchio)

US N= 1030

EU N= 990

Polineuropatia diabetica (DPN) N= 591

Randomizzato, aperto, controllato vs confronto attivo

Sicurezza a lungo-termine (1-2 anni, OA o LBP) N= 1121

Buynak R, 2010

Inte

ns

ità

de

l d

olo

re m

ed

io (

me

dia

+/-

SE

)

Placebo

Tapentadolo ER Oxycodone CR

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

- - - - - - - - - - - - - - - -

Basale

-

-

-

-

-

-

4

5

6

7

8

9

Titolazione (3 s) Mantenimento (12 s)

Prim. endpoint p<0.001

100-250mg

Tap PR BID

50-250mg

Tap PR BID

10-50mg

Oxy CR BID

20-50mg

Oxy CR BID

Efficacia analgesica

pari a quella di ossicodone

0

10

20

30

40

50

60

70

Tutti i sintomi Stipsi Nausea Vomito

Placebo

Tapentadolo PR

Ossicodone CR

Pazie

nti c

on e

venti a

vvers

i (%

)

*

* *

*

* p = <0.001 T Vs O

Lange B, 2010

Tollerabilità di TAPENTADOLO è superiore

0

2

4

6

8

10

12

14

16

18

Tapentadolo PR

Ossicodone

Va

ria

zione

vs

ba

sale

(LS

Mea

n)

Lange B, 2010

**

** **

**

**

**

**

** p<0.05 T vs O

Miglior QoL rispetto ad un oppioide forte

Conclusioni

• Dolore e depressione sono una cosa sola

• Valutazione sempre di entrambi

• Antidepressivi sono efficaci antalgici

• Alcuni analgesici sono antidepressivi

• Sapere, saper fare, saper essere

J Royal Soc Med, 2007

giovanni.gambassi@rm.unicatt.it

giovanni_gambassi@brown.edu