Original Article

Cold Pain Threshold and Role of NMDA Receptor Antagonists

Abstract

Clonidine, the α2-adrenergic agonist, is usually used as an antihypertensive drug. Dextromethorphan is a non-competitive NMDA antagonist which is routinely prescribed to suppress cough. However, there are not confidential documents regarding their analgesic effects. Due to the controversies over the analgesic properties of these two drugs, this study was designed to evaluate cold pain threshold changes following their administration. This study was conducted to assess the impact of oral clonidine and dextromethorphan on ice-water immersion tolerance. Four closed sachets labeled with codes were dedicated to each participant. Each of these four sachets contained placebo, 0.3 mg/kg dextromethorphan, 0.2 mg clonidine or both of the previous drugs randomly. The cold pain threshold was measured five times for each participant, once before taking any drug (T1) and the next four times (T2-T5) after taking each of the four sachets. 35 volunteers (15 men and 20 women) participated in the study. The study showed that cold pain threshold was higher in men than women (P=0.004) and also in participants above 30 than those under 30-year-old (P=0.007). Moreover, the pain threshold did not change significantly after the administration of clonidine (P=0.33) or dextromethorphan (P=0.21), but the threshold significantly increased after receiving a combination of dextromethorphan and clonidine compared with placebo overall (P=0.001). Cold pain threshold was higher in men and individuals over than 30-year-old and decreased significantly after administration of clonidine and dextromethorphan conjointly. Body mass index has no relation with changes in cold pain threshold by taking mentioned medications.

References :

Miller RD. Miller's anesthesia 2015,p1901.

Deborah B. McGuire, Connie Henke Yarbro, Ferrell B. Cancer Pain Management: Jones & Bartlett Learning; 1995.

Gintzler AR. Endorphin-mediated increases in pain threshold during pregnancy. Science. 1980;210(4466):193-195.

John E.Hall. Guyton and Hall Textbook of Medical Physiology.13th edition.2016; p630,631

McMurray GA, Jaques LB. Capillary resistance and blood pressure changes associated with pain due to local cooling: cold pressor test. Journal of Applied Physiology. 1959;14(5):813-816.

Simone DA, Kajander KC. Responses of cutaneous A-fiber nociceptors to noxious cold. J Neurophysiol. 1997;77(4):2049-2060.

Wolf S, Hardy JD. Studies on Pain. Observations on Pain Due to Local Cooling and on Factors Involved in the "Cold Pressor" Effect. J Clin Invest. 1941;20(5):521-533.

Hines EA, Jr, Brown GE. A standard test for measuring the variability of blood pressure: Its significance as an index of the prehypertensive state*. Annals of Internal Medicine. 1933;7(2):209-217.

Kreh A, Anton F, Gilly H, Handwerker HO. Vascular reactions correlated with pain due to cold. Experimental Neurology. 1984;85(3):533-546.

Lovallo W. The cold pressor test and autonomic function: a review and integration. Psychophysiology. 1975;12(3):268-282.

Farzin D, Mehrabian M. Ëvaluation of opioid and dopaminergic mechanisms of dextromethorphan on the nociceptive response-induced by hot plate in mice. Journal of Mazandaran University of Medical Sciences. 2004;14(45):1-15.

Hao JX, Yu W, Xu XJ, Wiesenfeld-Hallin Z. Effects of intrathecal vs. systemic clonidine in treating chronic allodynia-like response in spinally injured rats. Brain Res. 1996;736(1-2):28-34.

Siiba S, Nakanishi O, Ishikawa T, Hirakawa T, Kawahara H, Imamura Y. Increase in the threshold of pain and touch sensation in the human face with clonidine plus 30% nitrous oxide. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87(3):294-298.

Walker SM, Grafe M, Yaksh TL. Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. Anesth Analg. 2012;115(2):450-460.

Kumar A, Maitra S, Khanna P, Baidya DK. Clonidine for management of chronic pain: A brief review of the current evidences. Saudi J Anaesth. 2014;8(1):92-96.

Ilkjaer S, Bach LF, Nielsen PA, Wernberg M, Dahl JB. Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain. 2000;86(1-2):19-24.

Church J, Jones MG, Davies SN, Lodge D. Antitussive agents as N-methylaspartate antagonists: further studies. Canadian Journal of Physiology and Pharmacology. 1989/06/01 1989;67(6):561-567.

Wong BY, Coulter DA, Choi DW, Prince DA. Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices. Neurosci Lett. 1988;85(2):261-266.

Elliott KJ, Brodsky M, Hynansky A, Foley KM, Inturrisi CE. Dextromethorphan shows efficacy in experimental pain (nociception) and opioid tolerance. Neurology. December 1, 1995 1995;45(12 Suppl 8):S66-S68.

Elliott KJ, Brodsky M, Hynansky AD, Foley KM, Inturrisi CE. Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mRNA. Pain. 1995;61(3):401-409.

Duedahl TH, Dirks J, Petersen KB, Romsing J, Larsen NE, Dahl JB. Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect. Pain. 2005;113(3):360-368.

Hughes AM, Rhodes J, Fisher G, Sellers M, Growcott JW. Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers. Br J Clin Pharmacol. 2002;53(6):604-612.

Duedahl TH, Romsing J, Moiniche S, . DJ. A qualitative systematic review of peri-operative dextromethorphan in post-operative pain. Acta Anaesthesiol Scand. 2006;50:1-13.

Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83(3):389-400.

Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997;48(5):1212-1218.

Kauppila T, Gronroos M, Pertovaara A. An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist. Pharmacol Biochem Behav. 1995;52(3):641-644.

Ilkjaer S, Dirks J, Brennum J, Wernberg M, Dahl JB. Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans. Br J Anaesth. 1997;79(5):600-605.

McConaghy PM, McSorley P, McCaughey W, Campbell WI. Dextromethorphan and pain after total abdominal hysterectomy. Br J Anaesth. 1998;81(5):731-736.

Entezary SR, Farshadpour S, Alebouyeh MR, Imani F, Emami Meybodi MK, Yaribeygi H. Effects of preoperative use of oral dextromethorphan on postoperative need for analgesics in patients with knee arthroscopy. Anesth Pain Med. 2013;4(1).

Weinbroum AA, Lalayev G, Yashar T, Ben-Abraham R, Niv D, Flaishon R. Combined pre-incisional oral dextromethorphan and epidural lidocaine for postoperative pain reduction and morphine sparing: a randomised double-blind study on day-surgery patients. Anaesthesia. 2001;56(7):616-622.

De Negri P, Ivani G, Visconti C, De Vivo P, Lonnqvist PA. The dose-response relationship for clonidine added to a postoperative continuous epidural infusion of ropivacaine in children. Anesth Analg. 2001;93(1):71-76.

Stocche RM, Garcia LV, Klamt JG, dos Reis MP, Gil DR, Mesquita KL. Influence of intravenous clonidine in the cost of sevoflurane anesthesia for outpatient middle ear procedures. Rev Bras Anestesiol. 2004;54(1):91-98.

Carroll D, Jadad A, King V, Wiffen P, Glynn C, McQuay H. Single-dose, randomized, double-blind, double-dummy cross-over comparison of extradural and i.v. clonidine in chronic pain. Br J Anaesth. 1993;71(5):665-669.

Eisenach JC, Hood DD, Curry R. Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg. 1998;87(3):591-596.

Bernard MDJ-M, Hommeril MDJ-L, Passutl MDPDN, Pinaud MDPDM. Postoperative Analgesia by Intravenous Clonidine. Anesthesiology. 1991;75(4):577-582.

Compton P, Charuvastra VC, Ling W. Effect of oral ketorolac and gender on human cold pressor pain tolerance. Clin Exp Pharmacol Physiol. 2003;30(10):759-763.

Files
IssueVol 56, No 11 (2018) QRcode
SectionOriginal Article(s)
Keywords
Dextromethorphan Clonidine Cold pain threshold
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Nazemi P, Orandi AH, Orandi AA, Zanjani AP, Majedi H, Rahimi M, Karvandian K, Yousefshahi F, Sedighian A, Emami SA. Cold Pain Threshold and Role of NMDA Receptor Antagonists. Acta Med Iran. 2019;56(11):720-725.