Dose-dependent analgesic activity of mexiletine on thermally induced pain in rats
Keywords:Analgesia, Analgesiometer, Ibuprofen, Mexiletine, Tail flick
Background: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. In spite of many advances in pain research, we are unable to deal in an effective way. The cost for new drug development is increasing day by day. Drug repurposing is an approach to look for new use in drugs that are already approved for other indications. Mexiletine is a sodium channel blockers that is being approved for treatment of arrhythmias. It is being tried in treatment of various painful conditions. The present study is to evaluate the dose-dependent analgesic activity of mexiletine with ibuprofen.
Methods: The analgesic activity of mexiletine was compared at doses of 15mg/kg, 30mg/kg and 45mg/kg with the standard dose of ibuprofen at 10mg/kg in male Wistar rats in thermal model of tail flick analgesiometer.
Results: At lower doses (15mg/kg) of mexiletine, analgesic activity of ibuprofen was significantly higher. At higher doses (30 mg/kg and 45 mg/kg) of mexiletine, it was observed that there is no significant difference between the analgesic activities of both drugs.
Conclusions: Mexiletine demonstrated a dose-dependent analgesic activity. There was no statistically significant difference between the analgesic activities of higher doses of mexiletine when compared to ibuprofen.
Merskey H, Bogduk N. Classification of Chronic Pain. 2nd ed. Seattle, WA:IASP Press;2004:207.
Wolkerstorfer A, Handler N, Buschmann H. New approaches to treating pain. Bioorg Med Chem Lett. 2016 Feb 15;26(4):1103-19.
Bannwarth B, Kostine M. Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists? Drugs. 2014 Apr;74(6):619-26.
Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Res Rev. 2009 Apr 1;60(1):267-77.
Workman P, Draetta GF, Schellens JH, Bernards R. How much longer will we put up with $100,000 cancer drugs?. Cell. 2017 Feb 9;168(4):579-83.
Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology- patient and health systems opportunities. Nat Rev Clin Oncol. 2015 Dec;12(12):732-42.
Sisignano M, Parnham MJ, Geisslinger G. Drug Repurposing for the Development of Novel Analgesics. Trends Pharmacol Sci. 2016 Mar;37(3):172-83.
Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: implications for mechanisms of pain. Pain. 2007 Oct;131(3):243-57.
Kowey PR, Marinchak RA, Rials SJ, Bharucha DB. Classification and pharmacology of antiarrhythmic drugs. Am Heart J. 2000 Jul;140(1):12-20.
Camerino DC, Tricarico D, Desaphy JF. Ion channel pharmacology. Neurother J Am Soc Exp Neurother. 2007 Apr;4(2):184-98.
Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003345.
Romman A, Salama-Hanna J, Dwivedi S. Mexiletine Usage in a Chronic Pain Clinic: Indications, Tolerability, and Side Effects. Pain Physician. 2018 Sep;21(5):E573-9.
Waxman SG, Merkies ISJ, Gerrits MM, Dib-Hajj SD, Lauria G, Cox JJ, et al. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol. 2014 Nov;13(11):1152-60.
Weiss M, Simmons Z, Atassi N, Graves M, Parziale N, Salameh J, et al. A phase 2 study of mexiletine in sporadic amyotrophic lateral sclerosis (S50. 004). Neurol. 2015 Apr 6;84(14 Supplement):S50-004.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteer. Center for Drug Evaluation and Research, Pharmacology and Toxicology; 2005. Available at: https://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf%23search=%27guidekines+for+industry+sfe+starting%27. Accessed 2 November 2018.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31.
Vogel H, editor. Analgesic, Anti-inflammatory and Anti-pyretic activity. Drug Discovery and Evaluation: Pharmacological Assays. 3rd edition 2008. Berlin; New York:Springer;2007:983-1113.
Olschewski A, Schnoebel-Ehehalt R, Li Y, Tang B, Bräu ME, Wolff M. Mexiletine and lidocaine suppress the excitability of dorsal horn neurons. Anesth Analg. 2009 Jul;109(1):258-64.
Laird JM, Carter AJ, Grauert M, Cervero F. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats. Br J Pharmacol. 2001 Dec;134(8):1742-8.
Shaheed CA, Maher CG, Williams KA, Day R, McLachlan AJ. Efficacy, tolerability, and dose-dependent effects of opioid analgesics for low back pain: a systematic review and meta-analysis. JAMA Intern Med. 2016 Jul 1;176(7):958-68.
Elhwuegi AS, Hassan KM. The analgesic effect of different antidepressants combined with aspirin on thermally induced pain in Albino mice. Libyan J Med. 2012;7.
Eljezi V, Biboulet C, Boby H, Schoeffler P, Pereira B, Duale C. The Dose-Dependent Effects of Ketoprofen on Dynamic Pain after Open Heart Surgery. Pain Physician. 2017;20(6):509-20.
Thürauf N, Fleischer WK, Liefhold J, Schmid O, Kobal G. Dose dependent time course of the analgesic effect of a sustained-release preparation of tramadol on experimental phasic and tonic pain. Br J Clin Pharmacol. 1996 Feb;41(2):115-23.
Seymour RA, Ward-Booth P, Kelly PJ. Evaluation of different doses of soluble ibuprofen and ibuprofen tablets in postoperative dental pain. Br J Oral Maxillofac Surg. 1996 Feb;34(1):110-4.
Weiss MD, Macklin EA, Simmons Z, Knox AS, Greenblatt DJ, Atassi N, et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology. 2016 Apr 19;86(16):1474-81.
Roselli M, Carocci A, Budriesi R, Micucci M, Toma M, Di Cesare Mannelli L, et al. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues. Eur J Med Chem. 2016 Oct 4;121:300-7.