Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study
Avaliação dos efeitos neurotóxicos da administração intratecal do (S)-(+)-cetoprofeno em medula espinhal de rato: estudo experimental randômico e controlado
Cengiz Kaya, Yunus O. Atalay, Bilge C. Meydan, Yasemin B. Ustun, Ersin Koksal, Sultan Caliskan
Abstract
Background and objectives: Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting nonsteroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats. Methods: A randomized placebo-controlled experimental study was conducted. SpragueDawley rats (250---300 g) aged 12---16 weeks were randomly divided into 2 treatments [100 and 800g (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis. Results: Rats in all the groups exhibited normal pinch-toe testing response (score = 0) and normal gait at each observed time (motor function evaluation score = 1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p = 0.044; 2, 5, 0, p = 0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800 g group than those in the 100g and Control Groups (5, 3, 0, p = 0.048, respectively). Conclusion: Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.
Keywords
Resumo
Justificativa e objetivos: A administração intratecal de anti-inflamatórios não esteroides é mais eficaz no tratamento da dor pós-operatória. Anti-inflamatórios não esteroides, como o (S)- (+)-cetoprofeno, pode ser eficaz em doses intratecais inferiores às parenterais. A segurança pré-clínica relativa à possível neurotoxicidade associada ao (S)-(+)-cetoprofeno intratecal não foi avaliada. Neste estudo avaliamos a neurotoxicidade do (S)-(+)-cetoprofeno administrado por via intratecal em ratos. Métodos: Conduzimos um estudo experimental randomizado e controlado por placebo em ratos Sprague-Dawley (250---300 g) com idades entre 12 e 16 semanas. Eles foram randomicamente divididos em dois grupos de tratamento [100 e 800g de (S)-(+)-cetoprofeno] e um de controle (água estéril). Cateteres intratecais foram colocados através do espaço atlantoaxial nos ratos anestesiados. Testes de pinça, avaliações da função motora e exames histopatológicos da medula espinhal e das raízes nervosas foram realizados nos dias 3, 7 e 21 do estudo. Os cortes da medula espinhal foram avaliados por microscopia de luz para vacuolização do funículo axonal dorsal, perda de mielina axonal, cromatólise neuronal, neurite, inflamação, aderências e fibrose das meninges. Resultados: Em todos os grupos, os ratos exibiram resposta normal ao teste de pinça (pontuação = 0) e marcha normal em cada tempo observado (escore de avaliação da função motora = 1). A neurotoxicidade foi maior com os tratamentos nos dias 3 e 7 que no dia 21 (2, 3, 0, p = 0,044; 2, 5, 0, p = 0,029, respectivamente). No dia 7, os escores totais refletindo o dano neuronal foram maiores no grupo com 800 g que nos grupos com 100 g e controle (5, 3, 0, p = 0,048, respectivamente). Conclusão: A administração intratecal de (S)-(+)-cetoprofeno causou alterações neurohistopatológicas dose-dependentes em ratos nos dias 3 e 7 após a aplicação sugerindo que o (S)-(+)-cetoprofeno não deve ser administrado por via intratecal.
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References
1. Ceyhan D, Gulec MS. Is postoperative pain only a nociceptive pain? Agri. 2010;22:47---52.
2. Gan TJ, Habib AS, Miller TE, et al. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2014;30:149---60.
3. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131---57.
4. Yucel E, Kol IO, Duger C, et al. Ilioinguinal-iliohypogastric nerve block with intravenous dexketoprofen improves postoperative analgesia in abdominal hysterectomies. Rev Bras Anestesiol. 2013;63:334---9.
5. Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther. 1992;263:136---46.
6. Zhu X, Conklin D, Eisenach JC. Cyclooxygenase-1 in the spinal cord plays an important role in postoperative pain. Pain. 2003;104:15---23.
7. Mauleon D, Artigas R, Garcia ML, et al. Preclinical and clinical development of dexketoprofen. Drugs. 1996;52 Suppl 5:24---46.
8. Barbanoj MJ, Antonijoan RM, Gich I. Clinical pharmacokinetics of dexketoprofen. Clin Pharmacokinet. 2001;40:245---62.
9. Eisenach JC, Curry R, Tong C, et al. Effects of intrathecal ketorolac on human experimental pain. Anesthesiology. 2010;112:1216---24.
10. Eisenach JC, Curry R, Hood DD, et al. Phase I safety assessment of intrathecal ketorolac. Pain. 2002;99:599---604.
11. Eisenach JC, Curry R, Rauck R, et al. Role of spinal cyclooxygenase in human postoperative and chronic pain. Anesthesiology. 2010;112:1225---33.
12. Mazario J, Gaitan G, Herrero JF. Cyclooxygenase-1 vs. cyclooxygenase-2 inhibitors in the induction of antinociception in rodent withdrawal reflexes. Neuropharmacology. 2001;40:937---46.
13. Cabre F, Fernandez MF, Calvo L, et al. Analgesic, antiinflammatory, and antipyretic effects of S(+)-Ketoprofen in vivo. J Clin Pharmacol. 1998;38:3S---10S.
14. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976;17:1031---6.
15. Korkmaz HA, Maltepe F, Erbayraktar S, et al. Antinociceptive and neurotoxicologic screening of chronic intrathecal administration of ketorolac tromethamine in the rat. Anesth Analg. 2004;98:148---52.
16. Bajrovic F, Sketelj J. Extent of nociceptive dermatomes in adult rats is not primarily maintained by axonal competition. Exp Neurol. 1998;150:115---21.
17. Chatani K, Kawakami M, Weinstein JN, et al. Characterization of thermal hyperalgesia, c-fos expression, and alterations in neuropeptides after mechanical irritation of the dorsal root ganglion. Spine. 1995;20:277---90.
18. Guevara-Lopez U, Covarrubias-Gomez A, Gutierrez-Acar H, et al. Chronic subarachnoid administration of 1- (4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid (indomethacin): an evaluation of its neurotoxic effects in an animal model. Anesth Analg. 2006;103:99---102.
19. Kim YH, Lee PB, Park J, et al. The neurological safety of epidural parecoxib in rats. Neurotoxicology. 2011;32:864---70.
20. Hou Y, Wang L, Gao J, et al. A modified procedure for lumbar intrathecal catheterization in rats. Neurol Res. 2016;38:725---32.
21. Chen L, Yang G, Grosser T. Prostanoids and inflammatory pain. Prostaglandins Other Lipid Mediat. 2013;104---105:58---66.
22. Dodou K. Intrathecal route of drug delivery can save lives or improve quality of life. Pharm J. 2012;289:501.
23. Kang YJ, Vincler M, Li X, et al. Intrathecal ketorolac reverses hypersensitivity following acute fentanyl exposure. Anesthesiology. 2002;97:1641---4.
24. Aygun D, Kaplan S, Odaci E, et al. Toxicity of non-steroidal anti-inflammatory drugs: a review of melatonin and diclofenac sodium association. Histol Histopathol. 2012;27:417---36.
25. Hodgson PS, Neal JM, Pollock JE, et al. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88:797---809.
26. Yaksh TL, Horais KA, Tozier N, et al. Intrathecal ketorolac in dogs and rats. Toxicol Sci. 2004;80:322---34.
27. Canduz B, Aktug H, Mavioglu O, et al. Epidural lornoxicam administration --- innocent. J Clin Neurosci. 2007;14:968---74.
28. Ossipov MH, Jerussi TP, Ren K, et al. Differential effects of spinal (R)-Ketoprofen and (S)-Ketoprofen against signs of neuropathic pain and tonic nociception: evidence for a novel mechanism of action of (R)-ketoprofen against tactile allodynia. Pain. 2000;87:193---9.
29. Shohin IE, Kulinich JI, Ramenskaya GV, et al. Evaluation of in vitro equivalence for drugs containing BCS class II compound ketoprofen. Dissolut Technol. 2011;18:26---9.
30. Rodriguez MJ, Arbos RM, Amaro SR. Dexketoprofen trometamol: clinical evidence supporting its role as a painkiller. Expert Rev Neurother. 2008;8:1625---40.
31. Takenami T, Yagishita S, Murase S, et al. Neurotoxicity of intrathecally administered bupivacaine involves the posterior roots/posterior white matter and is milder than lidocaine in rats. Reg Anesth Pain Med. 2005;30:464---72.
32. Doan LV, Eydlin O, Piskoun B, et al. Despite differences in cytosolic calcium regulation, lidocaine toxicity is similar in adult and neonatal rat dorsal root ganglia in vitro. Anesthesiology. 2014;120:50---61.
33. Abut YC, Turkmen AZ, Midi A, et al. Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord. Rev Bras Anestesiol. 2015;65:27---33.
34. Ozdogan L, Ayerden T, Ornek D, et al. The neurotoxic effect of intrathecal diclofenac sodium in rats. Kafkas Univ Vet Fak. 2011;17:309---14.
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