PAZIENTE 1
10
2
5
PAZIENTE 2
9
3
6
PAZIENTE 3
8
3
7
PAZIENTE 4
11
2
7
PAZIENTE 5
10
2
6
PAZIENTE 6
9
2
8
PAZIENTE 7
9
3
8
PAZIENTE 8
10
1
7
PAZIENTE 9
11
2
6
PAZIENTE 10
7
2
6
PAZIENTE 11
8
2
6
PAZIENTE 12
6
1
7
PAZIENTE 13
8
2
8
PAZIENTE 14
10
2
8
PAZIENTE 15
8
2
7
MEDIA (minuti)
9
2
7
Figura 11CONCLUSIONI
In questo studio sono stati confrontati tre gruppi ( gruppo ketamina, gruppo gabapentin e gruppo controllo) con lo scopo di valutare e confrontare l’incidenza e la gravità del dolore dopo somministrazione di Remifentanil.
Il confronto dei due gruppi, gabapentin e ketamina, con il gruppo controllo, basa la sua validità su precedenti studi effettuati su animali
e volontari nei quali viene evidenziata l‘importanza della ketamina e del gabapentin nel prevenire l’iperalgesia oppioide indotta.
I dati raccolti hanno messo in evidenza un dolore postoperatorio più importante, sia a riposo che al movimento, nei pazienti che ricevono remifental intraoperatorio senza interventi atti a prevenire l’iperalgesia postoperatoria, rispetto a quanti effettuano invece interventi specifici. Questo fenomeno si verifica sia in recovery room, che a 4-6 ore dall’intervento che a 7-9 ore dall’intervento. Dopo 12 ore la situazione diventa analoga e non si rilevano differenze nel dolore percepito dal gruppo controllo rispetto al dolore percepito dai gruppi ketamina o gabapentin. Confrontando invece i dati ottenuti da questi ultimi due gruppi si può evidenziare come il dolore a riposo rilevato nel gruppo ketamina risulti uguale al dolore riferito dal gruppo gabapentin nelle rilevazioni effettuate in recovery room e alle ore 20.00 (dodici ore dall’intervento) mentre risulta maggiore alle ore 15.00 (quattro sei ore dall’intervento) e alle ore 18.00 (6-9 ore dall’intervento). Il dolore rilevato al movimento risulta invece maggiore nel gruppo gabapentin nella rilevazione effettuata in recovery room, mentre tale valore si eguaglia nelle ore successive. Il prezzo da pagare per garantire un efficace controllo del dolore si realizza attraverso un maggior utilizzo del sistema PCA, infatti nel gruppo controllo si verifica una maggiore richiesta di boli di morfina che si traduce in un maggior numero di boli infusi e quindi di quantità totale di farmaco consumato. Inoltre, di particolare interesse, i boli di PCA richiesti e quindi la quantità totale di farmaco consumata risultano maggiori nel gruppo gabapentin rispetto al gruppo ketamina.
probabilmente dovuta a limitate escursioni respiratorie legate alla situazione algica.
La nausea e/o vomito hanno una maggiore incidenza nel gruppo controllo in cui si riscontra una percentuale pari al 47%, cioè sette persone su quindici hanno riferito nausea costante o vomito. Inoltre, analizzando i valori riferiti dagli altri due gruppi, è emerso che la percentuale di pazienti con nausea e vomito è superiore nel gruppo ketamina rispetto al gruppo gabapentin.
La sedazione nel gruppo ketamina e nel gruppo controllo rimane inalterata con un valore pari a 2, mentre risulta modificata nel gruppo gabapentin. In tale gruppo infatti assume valore pari a 2,4 ponendo l’attenzione su come tale farmaco possa risultare sedativo sui pazienti. Infatti cinque dei quindici pazienti hanno manifestato una forte sonnolenza nelle ore successive all’assunzione del gabapentin. Un aspetto interessante che emerge dallo studio è la presenza di allucinazioni sia visive che uditive nei pazienti che hanno ricevuto ketamina. Sono stati infatti riscontrati tre casi in cui i pazienti riferivano voci e scene inesistenti. Inoltre nel gruppo ketamina sono stati rilevati cinque casi di nistagmo subito dopo il risveglio.
I tempi di risveglio risultano più lunghi nel gruppo con ketamina (nove minuti), con notevole difficoltà nel far riacquistare al paziente l’autonomia respiratoria. Sono stati rilevati tempi più brevi per i pazienti del gruppo gabapentin (sette minuti) e ancora più brevi per il gruppo controllo (due minuti).
Concludendo gli oppioidi, oggi, non possono essere considerati esclusivamente per la loro capacità di diminuire il dolore, sia cronico che acuto, e in quest’ultimo, sia intra che post-operatorio, ma è necessario valutarne gli effetti clinici “collaterali”, ovvero la loro
possibilità di indurre nausea, vomito, costipazione, iperalgesia al fine di controllare e ridurre questi effetti. La problematica dell’iperalgesia, più conosciuta fino ad oggi nei trattamenti cronici, è comparsa nel paziente chirurgico soprattutto con l’uso del remifentantanil. La maggior attenzione ad un percorso perioperatorio, in cui siano valutati i tempi e modi di somministrazione degli analgesici sia intraoperatori che postoperatori, e l’azione positiva di farmaci adiuvanti può risolvere positivamente la problematica dell’iperalgesia.
BIBLIOGRAFIA
1.AKIL et al. Endogenous opioid :overview andcurrent issues; Drug Alcohol Depend 1998. Overview of the endogenous opioid system: anatomical biochemical and functional issues; Endorphins opiates and behavioural processes 1988
2.Goodman Analgesici oppioidi; Howard B. Gutstein e Huda Akil
3.Eichelbaum and Evert Influence of pharmacogenetics on drug disposition and response. Clin.Exp.Pharmacol.Physiol.1996
4.Caraco et al. Impact of ethnic origin and quinidine coadministration on codeine’s disposition and pharmacokinetic effects; Pharmacol.Exp.Ther 1999
5.Burkle et al. Remifentanil: a novel short acting μ opioid; Anesth.Analg.1996
6.Glass et al. A review of the pharmacokinetics and pharmacodynamics of remifentanil; Anesth.Analg.1999
7.Boysen et al. Buprenorphine antagonis of ventilatory depression following fentanil anesthesia; Acta Anesthesiol.Scand.1988
8.Sjogren et al. is development of hyperalgesia allodynia and myoclonus releted to morphine metabolism during long-term administration? Acta Anesthesiol.Scand.1998
9.Anna Du Penn,MN. Mechanism of opioid induced tolerance and hyperalgesia ; Pain Management Nursering 2007
10.Ossipov. Underlying mechanism of pronociceptive consequences of prolonged morphine exposure; Biopolymers 2005
11.Angst and Clarke Opioid induced hyperalgesia: a qualitative systematic review; Anesthesiology 2006
12.Dirks et al. Mechanism of post-operative pain: clinical indications for a contribution of central neuronal sensitization; Anesthesiology 2002
13. Chen L, Huang LYM: Sustained potentiation of NMDA receptor- mediated glutamate responses through activation of protein kinase C by a μ opioid. Neuron 1991
14. Mao J et al. Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 1995
15.Mc.Clean the colecystokinin antagonist proglumide enhances the endogenous efficacy of morphine in humans with cronic benign pain; Anesth.Analg.1998
16.Xiao-Jun Xu opioid hyperalgesia and tolerance versus 5-HT1a
receptor-mediated inverse tolerance; Trends in pharmacological Sciences 2003
16.Malberg AB Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenasi inhibition; Sciences 1992
17.Malberg AB Spinal action of non-steroidal anti-infiammatory drugs: evidence for a central role of prostanoids in nociceptive processing; Prog Pharmacol Clin Pharmacol 1993
18.Mao et al. Opioid-induced abnormal pain sensitivity; Current Pain and Headache Reports 2006
19.Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M,: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000
20.Cooper DW, Lindsay SL, Ryall DM, Kokri MS, Eldabe SS, Lear GA: Does intrathecal fentanyl produce acute cross-tolerance to i.v. morphine? Br J Anaesth 1997
21. Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M: No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001
22. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M: Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003
23. Petersen KL, Jones B, Segredo V, Dahl JB, Rowbotham MC: Effect of remifentanil on pain and secondary hyperalgesia associated with the heat-capsaicin sensitization model in healthy volunteers. Anesthesiology 2001
24. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M: Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003
25. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J: Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003
26. Koppert W, Angst M, Alsheimer M, Sittl R, Albrecht S, Schuttler J, Schmelz M: Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain 2003
27. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M: Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003
28.Hood DD, Curry R, Eisenach JC: Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003
29. Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt- Nielsen L, Curatolo M: Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003
30. Li X, Clark JD: Hyperalgesia during opioid abstinence: mediation by glutamate and substance p. Anesth Analg 2002
31. Li X, Angst MS, Clark JD: Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001
32. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M,: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000
33. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST: Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999
34. Cooper DW, Lindsay SL, Ryall DM, Kokri MS, Eldabe SS, Lear GA: Does intrathecal fentanyl produce acute cross-tolerance to i.v. morphine? Br J Anaesth 1997
35. Celerier E, Laulin J-P, Corcuff J-B, Le Moal M, Simonnet G: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci 2001
36. Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G: Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999
37. Celerier E, Simonnet G, Maldonado R: Prevention of fentanyl- induced delayed pronociceptive effects in mice lacking the protein kinase Cgamma gene. Neuropharmacology 2004
38. Laulin JP, Celerier E, Larcher A, Le Moal M, Simonnet G: Opiate tolerance to daily heroin administration: An apparent phenomenon
39. Laulin JP, Larcher A, Celerier E, Le Moal M, Simonnet G: Long- lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur J Neurosci 1998
40. Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G,: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology 2000
41. Rivat C, Laulin JP, Corcuff JB, Celerier E, Pain L, Simonnet G: Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine. Anesthesiology 2002
42. Li X, Angst MS, Clark JD: Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001
43. Ibuki T, Dunbar SA, Yaksh TL: Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997
44. Vanderah TW, Suenaga NM, Ossipov MH, Malan TP Jr., Lai J, Porreca F: Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 2001
45. Aley KO, Green PG, Levine JD: Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal. J Neurosci 1995
46. Aley KO, Levine JD: Different mechanisms mediate development and expression of tolerance and dependence for peripheral mu-opioid antinociception in rat. J Neurosci 1997
47. Aley KO, Levine JD: Multiple receptors involved in peripheral alpha 2, mu, and A1 antinociception, tolerance, and withdrawal. J Neurosci 1997
48. Arts KS, Holmes BB, Fujimoto JM: Differential contribution of descending serotonergic and noradrenergic systems to central Tyr-D-Ala2- Gly-NMePhe4-Gly-ol5 (DAMGO) and morphine-induced antinociception in mice. J Pharmacol Exp Ther 1991
49. Khasar SG, Wang JF, Taiwo YO, Heller PH, Green PG, Levine JD: Mu- opioid agonist enhancement of prostaglandin-induced hyperalgesia in the rat: A G-protein beta gamma subunit-mediated effect? Neuroscience 1995
50. Mao J, Price DD, Mayer DJ: Thermal hyperalgesia in association with the development of morphine tolerance in rats: Roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994 51. Aley KO, Levine JD: Dissociation of tolerance and dependence for opioid peripheral antinociception in rats. J Neurosci 1997
52. Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong C-M, Zhang E-T, Malan TP Jr., Ossipov MH, Lai J, Porreca F: Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 2000
53. Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong C-M, Zhang E-T, Malan TP Jr., Ossipov MH, Lai J, Porreca F: Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 2000
54. Rohde DS, McKay WR, Abbadie C, Basbaum AI: Contribution of sacral spinal cord neurons to the autonomic and somatic consequences of withdrawal from morphine in the rat. Brain Res 1997 55. Gardell LR, Wang R, Burgess SE, Ossipov MH, Vanderah TW, Malan TP, Jr., Lai J, Porreca F: Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002
56. Hao J-X, Yu W, Wiesenfeld-Hallin Z, Xu X-J: Treatment of chronic allodynia in spinally injured rats: Effects of intrathecal selective opioid receptor agonists. Pain 1998
57. Leighton GE, Hill RG, Hughes J: Intrathecal injection of a kappa opioid agonist produces hyperalgesia in the guinea pig. Eur J Pharmacol 1988
58. Hamann SR, Martin WR: Opioid and nicotinic analgesic and hyperalgesic loci in the rat brain stem. J Pharmacol Exp Ther 1992 59. Hamann SR, Martin WR: Analgesic actions of dynorphin A(1-13) antiserum in the rat brain stem. Brain Res Bull 1992
60. Hamann SR, Martin WR: Hyperalgesic and analgesic actions of morphine, U50-488, naltrexone, and (-)-lobeline in the rat brainstem. Pharmacol Biochem Behav 1994
61. Parvini S, Hamann SR, Martin WR: Pharmacologic characteristics of a medullary hyperalgesic center. J Pharmacol Exp Ther 1993
62. Arner S, Rawal N, Gustafsson LL: Clinical experience of long-term treatment with epidural and intrathecal opioids-A nationwide survey. Acta Anaesthesiol Scand 1988.
63. Sjogren P, Jensen NH, Jensen TS: Disappearance of morphine- induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists.
64. Sjogren P, Jonsson T, Jensen NH, Drenck NE, Jensen TS: Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine.
65. Wilson GR, Reisfield GM: Morphine hyperalgesia: A case report. Am J Hosp Palliat Care 2003
66. Sjogren P, Jensen NH, Jensen TS: Disappearance of morphine- induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994
67. Lawlor P, Walker P, Bruera E, Mitchell S: Severe opioid toxicity and somatization of psychosocial distress in a cancer patient with a background of chemical dependence. J Pain Symptom Manage 1997 68. Sjogren P, Thunedborg LP, Christrup L, Hansen SH, Franks J: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiol Scand 1998
69. Heger S, Maier C, Otter K, Helwig U, Suttorp M: Lesson of the week: Morphine induced allodynia in a child with brain tumour. BMJ 1999
70. Parisod E, Siddall PJ, Viney M, McClelland JM, Cousins MJ: Allodynia after acute intrathecal morphine administration in a patient with neuropathic pain after spinal cord injury. Anesth Analg 2003 71. Mercadante S, Ferrera P, Villari P, Arcuri E: Hyperalgesia: An emerging iatrogenic syndrome. J Pain Symptom Manage 2003
72. Woolf CJ: Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res 1981
73. Yaksh TL, Harty GJ, Onofrio BM,: High dose of spinal morphine produce a nonopiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1986
74. Yaksh TL, Harty GJ: Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Exp Ther 1988
75. Sakurada T, Watanabe C, Okuda K, Sugiyama A, Moriyama T, Sakurada C, Tan-No K, Sakurada S: Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors. Brain Res Mol Brain Res 2002
76. Hara N, Minami T, Okuda-Ashitaka E, Sugimoto T, Sakai M, Onaka M, Mori H, Imanishi T, Shingu K, Ito S: Characterization of nociceptin hyperalgesia and allodynia in conscious mice. Br J Pharmacol 1997
77. Andrews HL: The effects of opiates on the pain threshold in post- addicts. J Clin Invest 1943
78. Levine JD, Gordon NC, Fields HL: Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain. Nature 1979
79. Joshi GP, Duffy L, Chehade J, Wesevich J, Gajraj N, Johnson ER: Effects of prophylactic nalmefene on the incidence of morphine- related side effects in patients receiving intravenous patient- controlled analgesia. Anesthesiology 1999
80. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R: Opioid-sparing effects of a low-dose infusion of naloxone in patient- administered morphine sulfate. Anesthesiology 1997
81. Cepeda MS, Africano JM, Manrique AM, Fragoso W, Carr DB: The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain 2002 82. Cepeda MS, Alvarez H, Morales O, Carr DB: Addition of ultralow dose naloxone to postoperative morphine PCA: Unchanged analgesia
and opioid requirement but decreased incidence of opioid side effects. Pain 2004
83. Kayser V, Besson JM, Guilbaud G: Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund's adjuvant-induced arthritic rats). Brain Res 1987
84. Crain SM, Shen KF: Acute thermal hyperalgesia elicited by low- dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia. Brain Res 2001
85. Shen KF, Crain SM: Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence. Brain Res 1994
86. Kayser V, Guilbaud G: Dose-dependent analgesic and hyperalgesic effects of systemic naloxone in arthritic rats. Brain Res 1981
87. Woolf CJ: Analgesia and hyperalgesia produced in the rat by intrathecal naloxone. Brain Res 1980
88. Kayser V, Guilbaud G: Cross-tolerance between analgesic low doses of morphine and naloxone in arthritic rats. Brain Res 1987
89.Trafton:Postsynaptic signaling via the [mu]-opioid receptor. Neurosci 2000
90.Borgland: Acute opioid receptor desensitization and tolerance: is there a link? Clin.Exp Pharmacol.Physiol 2001
91.Gardnell: Sustained morphine exposure induces a spinal dynorphine dependeny enhancement of excitatory transmitter release from primary afferent fibers. Neurosci 2002
92.Joly: Remifentanil induced post-operative hyperalgesia and its prevention with small dose of ketamina. Anesthesiology 2005.
93.Singler: Modulation of remifentanil - induced post – infusion hyperalgesia by propofol. Anesthesia and Analgesia 2007.
94. Vinik HR : Rapid development of tolerance to analgesia during remifentanil infusion in humans, Anesthesia and Analgesia 1998.
95. Chia: intraoperative high dose fentanyl induces post operative fentanyl tolerance. Can J Anaesth 1999
96. Guignard: Acute opioid tolerance: introperative remifentanil increase post operative pain and morphine requirement Anesthesiology 2000.
97. Hansen: intra operative remifentanil might influence pain levels in the immediate post operative period after major abdominal surgery. Anaesthesiologica scandinavica 2005.
98. Hood: intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin – induced hiperalgesia. Anesthesia and Analgesia 2003.
99. Clerier : Long-lastin hyperalgesia induced by fentanyl in rats: Preventive effects of ketamine. Anesthesiology 2000.
100. Joly: Remifentanil induced post-operative hyperalgesia and its prevention with small dose of ketamina. Anesthesiology 2005.
101. Angst : Short term infusion of the μ-opioid-agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003.
102. Aveline : preoperative ketamine and morphine for post operative pain control after lumbar disk surgery . Pain 2006.
103. Becke : intraoperative low-dose S-ketamine has no preventive effects on post-operative pain and morphine consumption after major urological surgery in children. Paediatric anaesth.2005
104.Guillon : the effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major surgery. Anesthesia and Analgesia 2003
105. Dubuisson, D. and Dennis, S.G., 1977. , The formalin test: a quantitative study of analgesic effects of morphine, meperidine, and brain stem stimulation on rats and cats. Pain
106.Dubuisson, D. and Dennis, S.G., 1977. , The formalin test: a
quantitative study of analgesic effects of morphine, meperidine, and brain stem stimulation on rats and cats. Pain
107. McCall, W.D., Tanner, K.D. and Levine, J.D., 1996. , Formalin induces biphasic activity in C-fibers in the rat. Neurosci.
108. Hargreaves, K.R., Dubner, F., Brown, C., Flores, A.S. and Joris, J., 1988. , A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain
109. Woolf, C.J. and Wall, P.D., 1986. , Relative effectiveness of C- primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J. Neurosci.
110. Woolf, C.J. and Wall, P.D., 1986. , Relative effectiveness of C- primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J. Neurosci.
111. Singh, L., Field, M.J., Ferris, P., Hunter, J.C., Oles, R.J., Williams, R.G. and Woodruff, G.N., 1996. , The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed byFull-size image-serine. Psychopharmacolog
112.-113. Hwang, J.H. and Yaksh, T.L., 1997. , Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically- induced neuropathic pain model in the rat. Reg. Anesthesia
114.-115Xiao, W.-H., Bennett, G.J., 1997. Gabapentin relieves abnormal pain sensations via a spinal site of action in a rat model of painful peripheral neuropathy. Pain
116. Burkhard Gustorff, MD DEAA, Katharina Hoechtl, Cand med, Thomas Sycha, MD, Evangelos Felouzis, MD DEAA, Stephan Lehr, MSc, and Hans G. Kress, MD PhD. The Effects of Remifentanil and Gabapentin on Hyperalgesia in a New Extended Inflammatory Skin Pain Model in Healthy Volunteers PAIN MEDICIN
117. Troster: modulation of remifentanil-induced analgesia and post infusion Hyperalgesia by parecoxib in humans. Anesthesiology 2006. 118. Siantra RS: Preoperative rofecoxib oral suspension as an analgesic ad junct after lower abdominal surgery: the effects on effort-dependent pain and pulmonary function. Anesthesia and Analgesia 2003.
119. Smith : analgesic effects of parecoxib following total abdominal hysterectomy Anesthesiology 2003.