Studiul interactiunii Tramadolului cu Dexametazona si Tenoxicamul

Studiul interactiunii Tramadolului cu Dexametazona si Tenoxicamul

1 Scopul cercetarii

Glucocorticoidul s-a ales pentru potenta sa si pentru faptul ca se foloseste deseori in urgente ca si Tramadolul, iar Tenoxicamul s-a dorit a fi folosit ca si comparatie privind efectul antiinflamator al celor doi inhibitori ai ciclooxigenazei.

În cazul Dexametazonei , cunoscandu-se timpul de latenta prelungit al instalarii efectelor, dat fiind mecanismul sau de actiune ce depinde de un receptor nuclear, s-au tatonat diferite intervale de timp( 2 ore, 3 zile ) fata de administrarea Tramadolului pentru a surprinde o eventuala

dependenta de timpul de latenta al aparitiei efectelor.

2 Material si metoda

3 Calcularea datelor si evaluarea statistica

Formulele de calcul a diferentei semnificative in cazul testului „t” sunt urmatoarele: (1) , unde sunt media rezultatelor esantioanelor 1, respectiv 2.

Sd = eroarea standard a diferentei, care se calculeaza dupa formula:    (2)

in esantioanele 1, respectiv 2.

valoarea individuala in esantionul 1, respectiv 2.

Daca inlocuim in formula 1 valoarea erorii standard, conform formulei 2 obtinem:

Daca „t” calculat este superior celui din tabelul pentru gradele de libertate corspunzatoare se ia o diferenta semnificativa cu o probabilitate de eroare de 5% (p=0,05). În cazul in care cele 2 esantioane sunt egale numeric (), putem reprezenta acest numar egal de cazuri printr-o inlocuire si formula devine:

Astfel s-a calculat semnificatia statistica a diferentelor dintre efectul placebo si efectul tratamentelor singulare pe de o parte si , respectiv cea a diferentelor dintre efectul asocierilor si efectul placebo si, respectiv al tratamentelor singulare.

4 Substante si asocieri studiate

S-au administrat:

Tramadol in doza de 20si 40mg/kgc- s.c. , in regiunea dorsala.S-a folosit preparatul MABRON^ฎ (Medochimie-Lemasol, Cipru), fiole injectabile, dupa diluare cu ser fiziologic.

Dexametazona in doza de 1 si 2mg/kgc –i.p., sub forma preparatului DEXAMETAZONA^ฎ, fiole injectabile diluate cu ser fiziologic.

Tenoxicamul- TILCOTIL^ฎ (Hoffman La Roche, Elvetia), sub forma de flacoane pulbere, a fost dizolvat in solventul livrat de firma si apoi cu ser fiziologic si administra i.p. in doza de 5mg/kgc.

5 Rezultate experimentale

TRI – timpul de reactie initial (sec)

Δ TRM 30’ – diferenta timpului de reactie la 30’

Tratament /Doza

(mg/kgc)

Nr.

ani

male

TRI (sec)

M ES

TRM 30’

(sec)

M ES

TRM 60’ (sec)

M ES

Placebo (0,1ml/10gc)

Tramadol 20

Tramadol 40

Tratament /Doza

(mg/kgc)

Nr.

ani

male

TRI (sec)

M ES

TRM 30’

(sec)

M ES

TRM 60’ (sec)

M ES

Dexa 1 sim ip

Dexa 2 sim ip

Tratament /Doza

(mg/kgc)

Nr.

ani

male

DTRM 30

(sec)

M ES

D TRM 60’

(sec)

M ES

P    la

P la

Dexa 1 sim ip

NS*

NS*

Dexa 2 sim ip

NS*

NS*

Tratament /Doza

(mg/kgc)

Nr.

ani

male

TRI (sec)

M ES

TRM 30’

(sec)

M ES

TRM 60’ (sec)

M ES

Tenoxicam 5

Tenoxicam 5 +Tramadol 20

Tenoxicamul in doza de 5mg/kgc a realizat un TRM de 26,4ฑ2,8s la 30 min. si unTRM de 20,8ฑ2,6 la 2,6 la 60 min.(tabelul 3.1). Aceste date evaluate statistic arata o prelungire a timpului de reactie cu 9,8ฑ2,8s la 30 min. si cu 4,2ฑ2,7s la 60 min., ambele valori nesemnificative statistic fata de placebo (tabelul 3.2).Asocierea Tenoxicamului cu Tramadolul a determinat inregistrarea de un TRI de 14,9ฑ0,8s, iar la 30 si 60 min. timpi mai mari de aproximativ 32s la ambele testari (tabelul 3.1), dar nici una dintre ele statistic semnificative fata de Tramadol (tabelul 3.2).

Tratament /Doza

(mg/kgc)

Nr.

ani

male

DTRM 30

(sec)

M ES

D TRM 60’

(sec)

M ES

P    la

P la

Tenoxicam 5

NS*

NS*

Tenoxicam 5 +Tramadol 20

<0,001*

<0,001*

Dexa 1 + Tramadol 20

Dexa 2 + Tramadol 40

Tratament /Doza

(mg/kgc)

Nr.

ani

male

DTRM 30

(sec)

M ES

D TRM 60’

(sec)

M ES

P    la

P la

Dexa 1 + Tramadol 20

NS*

NS**

NS*

NS**

Dexa 2 + Tramadol 40

<0.02*

NS**

NS*

NS**

Tratament /Doza

(mg/kgc)

Nr.

ani

male

TRI (sec)

M ES

TRM 30’

(sec)

M ES

TRM 60’ (sec)

M ES

Dexa 1 (2h)

Dexa 1 (2h) + Tramadol 20

Dexa 2 (2 h)

Dexa 2 (2 h) + Tramadol 20

Tratament /Doza

(mg/kgc)

Nr.

ani

male

DTRM 30

(sec)

M ES

D TRM 60’

(sec)

M ES

P    la

P la

Dexa 1 (2h)

NS*

NS*

Dexa 1 (2h) + Tramadol 20

<0.05*

NS**

NS*

NS**

Dexa 2 (2 h)

<0,02*

<0,01*

Dexa 2 (2 h) + Tramadol 20

<0,001*

NS**

<0.001*

<0.05**

Tratament /Doza

(mg/kgc)

Nr.

ani

male

TRI (sec)

M ES

TRM 30’

(sec)

M ES

TRM 60’ (sec)

M ES

Dexa 1 (3 zile)

Dexa 1 (3 zile)+ Tramadol 20

Tratament /Doza

(mg/kgc)

Nr.

ani

male

DTRM 30

(sec)

M ES

D TRM 60’

(sec)

M ES

P    la

P la

Dexa 1 (3 zile)

NS*

NS*

Dexa 1 (3 zile)+ Tramadol 20

<0,01*

NS**

<0,01*

NS**

6 Concluzii experimentale

Fig.1 Interactiunea Dexametazonei (1 si 2mg/kgc) cu Tramadolul(concomitent

În fig.2 este reprezentata interactiunea Dexametazonei 1mg/kgc –administrata cu 2h inainte- cu Tramadolul. Combinatia a realizat o analgezie superioara doar fata de placebo si doar la testarea de la 30 de min., restul rezultatelor fiind nesemnificative fata de placebo sau fata de Tramadolul singular.

Fig.2 Interactiunea Dexametazonei 1mg/kgc(cu 2h inainte) cu Tramadolul

Cucuiet s , Monea m, Flueras c - Interactiunea tramadolului cu inhibitori selectivi ai enzimei COX2 in testul placii incalzite. Revista de Medicina si Farmacie, U.M.F. Tg.Mures, 2002, 48, supl. 1 :127

CUCUIET S, MONEA M, ZAHARIA D – Studiul interactiunii tramadolului cu medicamente care influenteaza neurotransmisia monoaminergica. Revista de Medicina si Farmacie, UMF Tg.Mures, 2003, 49, supl.1: 122

CUCUIET S, FESZT G, MONEA M – Interactiunea tramadolului cu unii blocanti ai canalelor calciului in testul placii incalzite, in curs de aparitie, Revista de Medicina si Farmacie, U.M.F.Tg.Mures

Cucuiet S, Feszt g – Influenta unor substante central-deprimante fenotiazinice asupra efectului antinociceptiv al tramadolului, in curs de aparitie, Revista de Medicina si Farmacie, UMF Tg.Mures

9. Desmeules JA, Piguet V, Collart L, Dayer P - Contribution of monoaminergic modulation to the analgesic effect of tramadol Br J Clin Pharmacol 1996, 41(1):7-12

10. Desmeules JA- The tramadol option. Eur J Pain 2000 , 4 Suppl A:15-21

11. Driessen B , Reimann W- Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 1992, 105(1):147-151
    
    

Driessen B, Reimann W, Giertz H - Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro, Br J Pharmacol, 1993,108(3):806-811

Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B - Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 1996, 46(11):1029-1036

GIANNONI C, WHITE S, ENNEKING FK- Does dexamethasone with preemptive analgesia improve pediatric tonsillectomy pain? Otolaryngol Head Neck Surg 2002 Mar 126:307-15

Gürses E, Sungurtekin H, Tomatir E, Balci C, Gönüllü M - The addition of droperidol or clonidine to epidural tramadol shortens onset time and increases duration of postoperative analgesia: [L'addition de dropéridol ou de clonidine à l'administration péridurale de tramadol raccourcit le délai d'installation et prolonge la durée de l'analgésie postopératoire]. Can J Anaesth 2003, 50(2):147-152

HARDY JR, REES E.- A prospective survey of the use of dexamethasone on a palliative care unit.Palliat. Med. 2001 Jan.15(1):3

HOLTE K, WERNER MU, LACOUTURE PG, KEHLET H- Dexamethasone prolongs local analgesia after subcutaneous infiltration of bupivacaine microcapsules in human volunteers. Anesthesiology 2002 Jun 96:1331-5

Hopwood SE, Owesson CA, Callado LF, McLaughlin DP , Stamford JA - Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function. J Psychopharmacol 2001, 15 (3):147-153

KARST M, KEGEL T, LUKAS A, LUDEMANN W, HUSSEIN S, PIEPENBROCK S- Effect of celecoxib and dexamethasone on postoperative pain after lumbar disc surgery. Neurosurgery 2003 Aug 53:331-6; discussion 336-7

Kayser V, Besson JM, Guilbaud G - Evidence for a noradrenergic component in the antinociceptive effect of the analgesic agent tramadol in an animal model of clinical pain, the arthritic rat. Eur J Pharmacol 1992, 224(1) :83-88

21. Lee CR, McTavish D, Sorkin EM - Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states Drugs 1993, 46(2):313-340

22. LEE Y, LAI HY, LIN PC, LIN YS, HUANG SJ, SHYR MH- A dose ranging study of dexamethasone for preventing patient-controlled analgesia-related nausea and vomiting: a comparison of droperidol with saline. Anesth Analg 2004 Apr 98:1066-71, table of contents
    
    

Liu ZM, Zhou WH, Lian Z,Mu Y, Ren ZH, Cao JQ, Cai ZJ - Drug dependence and abuse potential of tramadol. Chung Kuo Yao Li Hsueh Pao 1999, 20(1):52-54

LUPSA RI – Contributii la studiul farmacologic (experimental si clinic) al unor substante si asocieri medicamentoase cu efect analgetic. Teza de doctorat, UMF Tg.Mures, 1997 : 2-21, 31-42

25. Manocha A, Sharma KK, Mediratta PK - Tramadol, a centrally acting opioid: anticonvulsant effect against maximal electroshock seizure in mice. Indian J Physiol Pharmacol, 1998, 42 (3) :407-411

26. Mathews S, Al Mulla A, Varghese PK, Radim K, Mumtaz S - Postanaesthetic shivering-a new look at tramadol. Anaesthesia 2002, 57(4):394-398
    
    

27. MC CORMACK KEITH and HAY BURNE- Disociation between the antinociceptive and antiinflamatory drugs : Drugs, 41, (4), (1991), 533-547

28. MERCADANTE S, FULFARO F, CASUCCIO A.- The use of corticosteroids in home palliative care. Support Care Cancer 2001 Jul.9(5)386-9
    
    
29. P Oliva, C Aurilio, F Massimo, A Grella, S Maione, E Grella, M Scafuro, F Rossi, L Berrino - The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component Eur J Pharmacol, 2002, 445(3): 179-185.

30. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL- Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.J Pharmacol Exp Ther 1992, 260(1):275-285

31. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N - Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol J Pharmacol Exp Ther 1993, 267(1):331-340

32. Raffa RB - A novel approach to the pharmacology of analgesics. Am J Med 1996, 101(1A):40S-46S

33. Raffa RB, Haslego ML, Maryanoff CA, Villani FJ, Codd EE, Connelly CD, Martinez RP, Schupsky JJ, Buben JA, Wu WN, Takacs AN, Mckown LA - Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride. J Pharmacol Exp Ther 1996, 278 (3):1098-1104

Reimann W, Hennies HH Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol Biochem Pharmacol 1994, 47(12):2289-2293

Reimann W, Schneider F - Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine. Eur J Pharmacol 1998, 349(2-3):199-203

REYMOND L, CHARLES MA, BOWMAN J, TRESTON P.- The effect of dexamethasone on the longevity of syringe driver subcutaneous sites in palliative care patients.Med J Aust. 2003 May 19 178(10)486-9

Ripple MG, Pestaner JP, Levine BS, Smialek JE - Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 2000, 21 (4) :370-374

Rojas-Corrales MO, Gibert-Rahola J, Micó JA - Tramadol induces antidepressant-type effects in mice Life Sciences, 1998, 63(12) 175-180

39. Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, Roca-Vinardell A, Mico JA - Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol. Pain 2000, 88(2):119-124

40. Sagata K, Minami K, Yanagihara N, Shiraishi M, Toyohira Y, Ueno S, Shigematsu A - Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg 2002, 94(4):901-906

41. Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A - Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther 2001, 299(1):255-260

42. Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I - Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha7 receptors. Br J Pharmacol 2002, 136(2):207-216

43. SKINNER HB, SHINTANI EY- Results of a multimodal analgesic trial involving patients with total hip or total knee arthroplasty. Am J Orthop 2004 Feb 33:85-92; discussion 92

44. Sprague JE, Leifheit M, Selken J, Milks MM, Kinder DH, Nichols DE - In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol. Synapse 2002, 43(2):118-121

45. Tarkkila P, Tuominen M, Lindgren L - Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997, 9(7):582-585

46. Tarkkila P, Tuominen M, Lindgren L - Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998, 15

47. Teppema LJ, Nieuwenhuijs D, Olievier CN, Dahan A- Respiratory depression by tramadol in the cat: involvement of opioid receptors.
    Anesthesiology 2003, 98(2):420-427

48. Vaughan DJA, Shinner G, Thornton C, Brunner MD - Effect of tramadol on electroencephalographic and auditory-evoked response variables during light anaesthesia. British Journal of Anaesthesia, 2000, 85, ( 5) : 705-707

WALSH D, AVASHIA J.- Glucocorticoids in clinical oncology. Cleve Clin J Med. 1992 Sep-Oct;59(5):505-15