5th Gheorghe Marinescu Symposium National Neuroscience Society of Romania October 1st -3rd, 2009

PAIN THERAPY FROM MOLECULE TO CLINIC

PROFESSOR OSTIN C. MUNGIU VICTOR COJOCARU THE EXCELENCY CENTER FOR THE STUDY AND THERAPY OF PAIN IASSY

Pain

An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. (IASP)
Pain is a CNS disease that has to be aggressively treated, regardless it's causeAlan Bussbaum, 2005

What is pain?
Whatever the experiencing person says it is, existing whenever he says it does Margo McCaffrey

TYPES OF PAIN
symptom Pain disease physiologic

Pain
acute Pain pathologic

chronic

TYPES OF PAIN
somatic nociceptive visceral PAIN neuropathic

nonnociceptive
psychogenic R. Kannev, Pain Management Secrets, 1997

TYPES OF PAIN
Nociceptive pain nociceptors A delta fibres C fibres mecanical thermal chemical

Exogenic nociceptive stimuli

Nociceptive Pain
Serotonine Substance Bradikinine

Endogenic stimuli
(algogenic molecules)

PG
Ions: ATP histamine

H+ si K+

TIPURI DE DURERE

DUREREA SOMATIC
Bine localizat Ex:
Durere Durere

postoperatorie musculoscheletica

Durerea Durerea

din artrite

din metastazele osoase Durere de dini

McGill Pain Scale

Types of Pain
distension

Visceral Pain

traction torsion
Vague localization Cramps Skin reference (REFERRED PAIN) Autonomic NS symptoms (nausea, vomisments, cardiac rhythm disorders )

particularities:

Ex. Gastric , pancreatic, guts, billiary pain, urethral etc.

TYPES OF PAIN

NEUROPATHIC PAIN
Nerve

lesion Persistence sharp, shooting, electric, burning, stabbing like

Exemples:
Pain

in diabetus melitus, zoster Phantom Limb Pain Complex Regional Pain Syndrome CRPS

Phantom Limb Pain

TIPURI DE DURERE

Psychogenic pain

Unclear mechanism Psychiatric sympthoms Sensitive to psychotropic agents * empathy pain * social pain

PAIN MECHANISMS

FARMACOLOGIA DURERII

PERIFERIC STAGE

PERIFERIC STAGE

THE GATE CONTROL THEORY (WALL-MELZAK 1965)

PAIN MEDIATORS
CATEGORIA Neurotrasmitori DENUMIREA Neuromodulatori Serotonina (5HT) Histamina Acetilcolina (Ach) Glutamat Factorul de cretere nervoas (NGF) Peptidul legat genetic de calcitonin (CGRP) Tahikinine Substana P (receptor NK1) Neurokinina A (receptor NK2) Neurokinina B (receptor NK3) Bradikinine Bradikinine (receptor B1 i B2) OBERVAII Extrem de activ Mai puin activ, implicat mai ales n senzaia de mncrime Transmitor rapid al durerii Prezent n esuturi lezate, determin hiperalgezie Acioneaz central i periferic

Kinine

Transmitor lent al durerii

Prostaglandine

E F Leucotriene Acid lactic ATP, ADP Ionul de potasiu

Puternic algogene, acioneaz i prin eliberare prostaglandine. Se cupleaz cu un receptor specific cuplat cu proteina G. Recent a fost sintetizat un antagonist competitiv icatibant cu proprieti analgezice Nu sunt direct algogene dar poteneaz efectul algogen al serotoninei si kininelor Scderea pH-ului are efect nociceptiv prin deschiderea canalelor ionice activate de protoni (de exemplu canale de calciu). Sunt considerai mediatori poteniali ai durerii ischemice Se pare c n periferie poteneaz stimulii algici iar la nivel central poteneaz analgezia betaendorfinic.

Metabolii

Oxidul Nitric

PERCEPIA DURERII
CORTEX SUBCORTICAL NUCLEI

BRAINSTEM gate control SPINE

periphery
sensitizing factors algogene proalgogene Nociceptor

STIMULI

Muscles don't hurt, Joints don't hurt Tendons don't hurt

Only

nerve hurts!

PAIN EVALUATION

PAIN EVALUATION

1. Tritium labeled Bradykinine bonding test (RAT ILEON) 2. Tritium labeled substance P bonding test (pig brain) 3. Tritium labeled Naloxone bonding test (rat bran) 4. Tritium labeled Dihydromorphone bonding test (rat brain) 5 Tritium labeled Bromazopcine bonding test (guinea pig brain) 6. Enkephalinaze inhibition test (rat kidney) Compression tail Mechanoalgezic paw Hot plate Thermoalgezic Tail imertion Tail flick Writting test (acetic acid, bradykinine, Chemical benzochinone) Testul la formalin Podolorimetric Electphysiologic Rectodolometric Acute experimental arthritis Subacute experimental arthritis Escape and avoiding Mechanic tests Healthy voluntars Thermic tests Chemical tests Electrophysiologic tests Analogue visual Patients Scales scale Numeric visual scale

IN VITRO IN VIVO

IN HUMANS

IN LAB ANIMAL S

Behavioral analisis

Verbal vicual scale Tones visual scale Pictural scale Visuale mixed scale Simple Movement/posture Enviromental MMPI MPQ DDS Endorphines dosage Algezimey

Questionnaires

Lab biochemical evaluation

PAIN EVALUATION

PAIN EVALUATION

PAIN EVALUATION

PAIN EVALUATION

EVALUAREA DURERII

ENDOGENE OPIOIDS

OPIOIZII ENDOGENI
ProopiomelanocortinE (prehormonE 260 AA) ACTH -lipotropinE 91 AA MSH

ProenkefalinE A

-endorfinE 31 AA

Proenkefaline B (prodynorfine)

Enkefaline 5 AA leucin-metionin and also hecta/octa peptide

dynorfine neoendorfine

rimorfine

ENDOGENE OPIOIDS
PRECURSORs OP
Proopiomelancocortins (POMC) Proenkefalins (proENK)

GENES
3 exons 2 introns 4 exons 5 introns

OPIOPEPTIDES
-endorfins (-LPH61-76) -endorfins (-LPH61-96) Met-enkefaline (5aa) Leu-Enkefaline (5 aa) Heptapeptide (7 aa) Octapeptide (8 aa) Peptide I BAM-12P (Peptid I 15-26) BAM 20 (Peptid I 15-26) -neoendorfine (10 aa) -neoendorfine (9 aa) Dinorfine (32 aa) Dinorfine A (Dinorfina 117) -endorfine (-LPH51-77) -endorfinae (fragmentC) (-LPH51-87) BAM 22P (Peptide I 15-36) Peptide E (Peptide I 15-39) Metorfamide (Peptide E18NH2) Peptide F Peptid B Sinenkefalin (proenkefaline 1-70) Dinorfine B (Dinorfine 2032) Dinorfine 1-8 Levomorfine

Prodinorfins (proDYN) (proenkefalins B)

4 exons 3 introns

m-ARN

PREPROPEPTIDE

proENK

POMC

proDYN

R.E. Conversion enzymes

ENKEFALINE Presynaptic vesicles

Presynaptic stage Enkefalinaze Aminopeptidaze

Postsynaptic stage

Receptors: , ,

Opioid receptors
2nd

OP1

OP2

OP3

OP4

IUPHAR name
disphoric MOR KOR DOR XOR

2nd messengers

-Gi + AC -G K channels coupled morfine endorfin addiction

-Gi + AC -G Ca2+ channels coupled pentazoci n dinorfine -disforia, no addiction

-Gi + AC Ionicchannel s coupled Leuenkefalin a -spine

- Ca2+

channels blockers

agonists

nocicepti n (xenorfin) -ag. spinal -antag. supraspin al hiperalge zia

papaverin a -miorelax

effects

-ANS modifires

Endogene opioids

Analgesia

dynB29>dynA(1-32)>dynA(1-17)>dynB> neoendorfine

Food intake Liquid intake (taste modifiers)

Stress analgesia; betaendorfines Dependence, tolerance (~ ?) Learning, memory (modulation?) cardiovascular

Alcohol betaendorfines

Betaendorfines TA Dinorfine A TA

Anti coughing effect Hipothermic effece (dinorfina A, betaendorfines) GI propulsion inhibition.

Published results

%MPE (antinociception %). The effect of 1) Tyr-Gly, 0.5 mg/rat i.t., 2) Tyr-Gly-Gly, 0.5 mg/rat i.t., 3) Leu-enkefaline, 0.5 mg/rat i.t. on nociception, evaluated by mechano-algesic test in rats. Throughout the graphs, an asterisk indicates a significant antinociception (p < 0.05) compared with the control group. The horizontal line represents the 30% antinociception level.

Pain therapy
Class

Coanalgezice:

TCA; neuroleptics; anticonvulsivants; miorelaxants; calcitonine; adenozine; metoclopramid; corticoids; nitrits ; antacides; acetazolamide.

Calciu inhibitors; canabinoids; GABA-agonist;s L-dopa; capsaicine; antiarhytmics; antivirrals

Paraanalgezics:

Chronology
1803 1874 1939 1952 1971-1974 1974 -1975 1976-1986
Morphine

is isolated Serturner Heroine semisinteza Petidina sinteze Morphine- complete synthesis Opioid receptors are isolated Enkefalines are isolated Endorfines are isolated The list continues...

OPIOIDES

Morphine Morphine 6 glucuronid 3.7 s.c. 45 i.c.v. Foley 1993 CR Bashford 2001 Roxanol SR (8 ore) MS Contin (12 ore) MST Heroine metabolites: Morfine im 2 - 6 acetyl morphine

ANALGEZICE OPIOIDE

Hydromorfon 5 - avantaje la btrni (t1/2 1.5-2 ore) - analgezie excelent - efecte secundare minime (Brose 1991) Levorfanol 2 - n durerile cronice la cei ce nu tolereaz morfina - afinitate pe receptorii Codeine pentru treapta a II-a n combinaii DH codeina Oxycodone 10 codeina dureri moderate i severe - prezent n combinaii

ANALGEZICE OPIOIDE
Meperidina 75 mg = 10 mg morfina i.m. - normepteridin: metabolit activ convulsivant 2 - analgezic Metadona - 10mg = 10mg morfina - analgezic de linia a II-a - terapia addiciei Propoxifen durerea moderat 1/2 1/3 din codein -metabolit: norpropoxifen (convulsivant) Fentanyl 1:20, 1:30 fa de morfin - dureri intra i post operatorii - numeroase ci de administrare - metabolii inactivi

AGONITI /ANTAGONITI

Pentazocina 35 mg = 10 mg morfina. Receptori , TA disforie, efecte psihotomimetice Nalbufina echivalent cu morfina - pentru dureri postoperatorii - substitut al morfinei (mai puine efecte secundare) - potenial de abuz mai sczut ca morfina - potenial psihotomimetic sczut Butorfanol 2 mg i.m. = 10 mg morfin - potenial slab de dependen fizic - util n durerea acut la pacieni ce nu au mai primit opioide

NSAID`S

NO-NSAID`S

Primul NO-AINS sintetizat a fost nitroaspirina (Wallace i Granger, 1996) NCX 4016, NCX 4215 Tabel 4. Dezvoltarea NO-AINS aflate n stadiul de studii clinice

SCARA ANALGEZIC PENTRU CONTROLUL DURERII

III Hard opioid non-opioid

II Soft opioid non-opioid

Pain persists or increase

Non-opioid

Pain persists or increase

WHO SCALESCARA OMS

4. Invazive interventions Persistent or increasing pain

3. Hard opioids For moderate To severe pain

Persistent or increasing pain

2. Soft opioids for mild to moderate pain non-opioid analgesics

adjuvants

Persistent or increasing pain

1. Anon-opioid analgesics for mild pain

adjuvants

MORPHINE IN EUROPE

www.algezio.ro

NOT SUFFERING IS A HUMAN RIGHT

Pain has no moral or medical justification

LEGEA OPIOIDELOR

PHARMACOLOGIC ANALGESIC STRATEGIES FOR THE 3RD MILLENIUM

A.

A1 opioids receptors A2 excitatory aa rec A3 Pg and Lt rec A4 neurokines rec A5 NGF rec) A6 bradikinine rec A7 adenosine rec A8 colecistokinine rec A9 monoamines rec: 5HT1D, alfa2, dopaminergic rec A10 cholinergici rec A11 cannabinoid rec B1 COX 2 inhibitors B2 enkefalinaze inhibitors B3 NO syntase inhibitors
ENZYMATIC LEVEL

RECEPTOR LEVEL

B.

C. Ion channels Inhibitors/Activators Na channel inhibitors starting from local anesthetics or antidepressants; K channels activatorsu; Ca channels inhibitors (SNX-III, N channel bloker in spinal pain modulationl), Gohil, 1993, Malmerg, 1994. D. genetic level

DREAM GENE

DREAM gene (downstream regulatory element antagonist modulator) Transcriptional DNA repressantului. 2 DREAM variants in rats:

ORF 1 ORF 2 (Hammond P.I. et al., 2002) Cuting of prodinorfine exprimation in cell cultures (Campos D. et al., 2003) and at spine level (Costigan M. et al., 2002) Is repressing early c-fos genes (Carrion A.M. et al., 1999)

DREAM:

DREAM GENE

knockout (cu lipsa a genei DREAM) oarecii knockout manifest o reducere semnificativ a sensibilitii acute, a durerii inflamatorii i neuropate dar rspunsuri motorii, cardiace i imunitare normale. (Bradley D., 2002) animalele knockout prezint o atenuare marcat a nocicepiei la toate tipurile de stimuli testai (mecanici, termici, chimici) att pe modele de durere somatic ct i visceral. (Los Santos-Artega M. et al., 2003) rspunsurile la stimularea nociceptiv a oarecilor knockout sunt mediate prin receptorii k-opioizi (norbinaltorphimine dihydrochloride- antagonist selectiv k-opioid). (Brent A. et al., 2002)

GENA DREAM
Modularea funciei genei DREAM poate fi util n alterarea pragului de percepie dureroas direcii viitoare:

substane care ar putea bloca capacitatea de legare a DREAM de ADN; prevenirea producerii proteinei DREAM.

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