Anti-hyperalgesic effect of paracetamol in rat model of thermal hyperalgesia: implications for the treatment of neuropathic pain
Keywords:
Acetaminophen, Hyperalgesia, Neuropathic pain, Gabapentin, Paw withdrawal latencyAbstract
Background: Neuropathic pain conditions are prevalent in general population and difficult to treat. Most currently available therapies do not provide adequate benefit in all treated patients. Though Paracetamol is available for more than 100 years and have huge safety data, it is still not included in any treatment guidelines for neuropathic pain, as very few studies have evaluated its effects in neuropathic pain conditions. The aim of this study was to evaluate antihyperalgesic activity of paracetamol and to compare it with antihyperalgesic effect of amitriptyline and gabapentin in rat model of thermal hyperalgesia.
Methods: Male albino wistar rats weighing 200-250 g of body weight and 4-6 months old were used. After anaesthetizing rats with 2% halothane, mild thermal injury was induced using hot plate analgesiometer. Drugs were administered intraperitoneally 30 minutes after thermal injury. Paw withdrawal latencies were measured at 30, 60, 90 and 120 minutes after drug administration. Statistical analysis done using GraphPad Prism version 5.01 and one way ANOVA followed by post hoc Dunnett's test or Tukey's test were used.
Results: Paracetamol showed both dose as well as time dependent antihyperalgesic activity. Gabapentin demonstrated significantly more antihyperalgesic activity compared to amitriptyline (p< 0.05) and paracetamol (p< 0.01).
Conclusions: Paracetamol showed antihyperalgesic activity however, it was less as compared to drugs like gabapentin and amitriptyline. Considering the excellent safety profile of paracetamol, it might be useful adjuvant drug for treatment of neuropathic pain conditions.
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References
McCarberg BH, Billington R. Consequences of neuropathic pain: quality of life issues and associated costs. Am J Manag Care 2006;12(9 Suppl):S263-8.
Vinik A. The approach to the management of the patient with neuropathic pain. J Clin Endocrinol Metab 2010;95:4802-11.
Sarzi-Puttini P, Vellucci R, Zuccaro SM, Cherubino P, Labianca R, Fornasari D. The appropriate treatment of chronic pain. Clin Drug Investig 2012;32 Suppl 1:21-33.
Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep 2012;16:191-8.
Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative Sensory Testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010;150:439-50.
Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88.
Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011;3:CD007938. doi: 10.1002/14651858.CD007938.pub2.
Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007;4:CD005454. doi: 10.1002/ 14651858.CD005454.pub2.
Toussaint K, Yang XC, Zielinski MA, Reigle KL, Sacavage SD, Nagar S, Raffa RB. What do we (not) know about how paracetamol (acetaminophen) works? J Clin Pharm Ther 2010;35:617-38.
Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol 2007;573(1-3):214-5.
Lynch JJ 3rd, Wade CL, Zhong CM, Mikusa JP, Honore P. Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model. Pain 2004 J;110(1-2):56-63.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32:77-88.
Jun JH, Yaksh TL. The effect of intrathecal gabapentin and 3-isobutyl gamma-aminobutyric acid on the hyperalgesia observed after thermal injury in the rat. Anesth Analg 1998;86:348-54.
Dallocchio C, Buffa C, Mazzarello P, Chiroli S. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage 2000;20:280-5.
Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237-51.
O'Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009;122(10 Suppl):S22-32.
Vadalouca A, Raptis E, Moka E, Zis P, Sykioti P, Siafaka I. Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current literature. Pain Pract 2012;12:219-51.
Drug treatment of neuropathic pain. Drug Ther Bull 2000;38:89-93.
Coluzzi F, Mattia C. Mechanism-based treatment in chronic neuropathic pain: the role of antidepressants. Curr Pharm Des 2005;11:2945-60.
Verdu B, Decosterd I, Buclin T, Stiefel F, Berney
A. Antidepressants for the treatment of chronic
pain. Drugs 2008;68:2611-32.
Ayoub SS, Colville-Nash PR, Willoughby DA, Botting RM. The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice. Eur J Pharmacol 2006;538(1-3):57-65.
Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Biochem Biophys 2001;387:273-80.
Botting RM. Mechanism of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis 2000;31 Suppl 5:S202-10.
Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther 2006;79:9-19.
Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev 2006;12(3-4):250-75.
Mallet C, Daulhac L, Bonnefont J, Ledent C, Etienne M, Chapuy E, Libert F, Eschalier A. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 2008;139:190-200.
Bujalska M, Gumułka WS. Effect of cyclooxygenase and NO synthase inhibitors on antinociceptive action of acetaminophen. Pol J Pharmacol 2001;53:341-50.
Curros-Criado MM, Herrero JF. Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin. Br J Pharmacol 2009;158:601-9.
Matsunaga A, Kawamoto M, Shiraishi S, Yasuda T, Kajiyama S, Kurita S, Yuge O. Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats. Eur J Pharmacol 2007;554:12-7.
Im KS, Jung HJ, Kim JB, Lee JM, Park HJ, Joo CH, Moon DE. The antinociceptive effect of acetaminophen in a rat model of neuropathic pain. Kaohsiung J Med Sci 2012;28:251-8.
Raffa RB, Clark-Vetri R, Tallarida RJ, Wertheimer AI. Combination strategies for pain management. Expert Opin Pharmacother 2003;4:1697-708.
Gatti A, Sabato AF, Carucci A, Bertini L, Mammucari M, Occhioni R. Adequacy assessment of oxycodone/paracetamol (acetaminophen) in multimodal chronic pain: a prospective observational study. Clin Drug Investig 2009;29 (Suppl 1):31-40.
Romanò CL, Romanò D, Lacerenza M. Antineuropathic and antinociceptive drugs combination in patients with chronic low back pain: a systematic review. Pain Res Treat 2012;2012:154781.
Hama AT, Sagen J. Cannabinoid receptor-mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain. Neuropharmacology 2010;58(4-5):758-66.
Durmus M, Kadir But A, Saricicek V, Ilksen Toprak H, Ozcan Ersoy M. The post-operative analgesic effects of a combination of gabapentin and paracetamol in patients undergoing abdominal hysterectomy: a randomized clinical trial. Acta Anaesthesiol Scand 2007;51:299-304.