Evaluation of the analgesic activity of single and multiple oral doses of teneligliptin (20 mg/day), using hot air analgesiometer in healthy human volunteers: a randomized, double blind, placebo controlled, cross over study

Maleha Butul, Usharani Pingali, Chandrasekhar Nutalapati


Background DPP-4 inhibitors showed analgesic and anti-inflammatory activity in human and animal-studies. DPP-4 inhibitors improved nerve function and thermal nociception in animal models. Aim of the study was to explore analgesic activity of single and multiple doses of teneligliptin 20 mg/day using hot air analgesiometer in healthy human volunteers.

Methods: After IEC approval and informed consent, subjects were randomized to receive either teneligliptin 20 mg or placebo in double-blinded manner with standard breakfast. Mean pain threshold and tolerance(sec) using hot air analgesiometer were recorded at baseline and 1 hr, 2 hrs post drug on day 1, for single dose study. Subsequently drugs were administered under supervision daily for 6 days and same procedure repeated on day8 for multiple-dose study. After 2 weeks washout, subjects crossed over in period 2 to receive other formulation and same procedure repeated to determine study parameters. Fasting blood-sugar (FBS) was monitored, ADRs recorded in CRF. Statistical analysis done with SPSS20.0.

Results: Twelve-healthy subjects (8 males, 4 females) with mean age 33.08±4.69 years, mean BMI 22.6±1.37kg/m2 participated. Single dose teneligliptin produced significant increase in pain threshold (35.9%) and pain tolerance (25.1%) (p<0.001) at 1hour compared to baseline. With multiple doses, pain threshold increased by 37.1% and pain tolerance by 25.4% (p<0.001) at 1hour compared to baseline. The increase in pain threshold and tolerance values at 1 and 2 hours were similar. There was no significant change in pain threshold(p=0.4135) and tolerance (p=0.4476) at baseline on day1 and day 8. Placebo showed non-significant change in study parameters. Both treatments well tolerated. FBS of volunteers within normal limits during treatment period and no hypoglycemia reported.

Conclusions: Results of our study suggest that teneligliptin20mg in healthy subjects demonstrated modest analgesic activity compared to baseline and placebo. Its role in painful diabetic conditions may be further explored.


Analgesic, Teneligliptin, GLP-1, Thermal nociception, Healthy volunteers, Hot air analgesiometer

Full Text:



Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Internal Med. 1993;153(4):477-84.

Balakumar P, Dhanaraj SA. Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials. Cellular signalling 2013;25(9):1799-803.

Kim SJ, Nian C, Doudet DJ, McIntosh CH. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes. 2009;58(3):641-51.

Makdissi A, Ghanim H, Vora M, Green K, Abuaysheh S, Chaudhuri A, et al. Sitagliptin exerts an antinflammatory action. The J Clin Endocrinol Metabol. 2012;97(9):3333-41.

Wang X, Hausding M, Weng SY, Kim YO, Steven S, Klein T, et al. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxidants Redox Signaling. 2018;28(2):87-109.

Újhelyi J, Újhelyi Z, Szalai A, László JF, Cayasso M, Vecsernyés M, et al. Analgesic and anti-inflammatory effectiveness of sitagliptin and vildagliptin in mice. Regulatory Peptides. 2014;194:23-9.

Nabeno M, Akahoshi F, Kishida H, Miyaguchi I, Tanaka Y, Ishii S, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophy Res Communications 2013;434(2):191-6.

Sharma SK, Panneerselvam A, Singh KP, Parmar G, Gadge P, Swami O.C. Teneligliptin in management of type 2 diabetes mellitus. Diabetes, Metabolic Syndrome and Obesity: Targets Therap. 2016;9:251-60.

Erin E, Mulvihill, Daniel J. Drucker. Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors. Endocrine Rev. 2014;35:992-1019.

Staahl C, Drewes AM. Experimental Human Pain Models: A Review of Standardised Methods for Preclinical Testing of Analgesics. Basic Clin Pharmacol Toxicol. 2004;95:97-111.

Reddy KSK, Naidu MUR, Rani PU, Rao TRK. Human experimental pain models: A review of standardized methods in drug development. J Res Med Sci. 2012;17:587-95.

Usharani P, Nalini P, Manjunath N, Reddy S. Evaluation of the analgesic activity of standardized aqueous extract of Withania somnifera in healthy human volunteers using Hot Air Pain Model. Res J Life Sci. 2013;1:1-6.

Renate VG, Diane MG, Daniel VR, Diamant M. Extra‐pancreatic effects of incretin‐based therapies: potential benefit for cardiovascular‐risk management in type 2 diabetes. Diabetes Obesity Metabol. 2013;15(7):593-606.

Kamble M, Gupta R, Rehan HS, Gupta LK. Neurobehavioral effects of liraglutide and sitagliptin in experimental models. Euro J Pharmacol. 2016.

Byrne FM, Cheetham S, Vickers S, and Chapman V. Characterisation of Pain Responses in the High Fat Diet/Streptozotocin Model of Diabetes and the Analgesic Effects of Antidiabetic Treatments. J Diabetes Res. 2015;1-13.

Sharmaa AK, Sharmaa A, Kumaria R, Kishorea K, Sharmaa D, Srinivasan BP, et al. Sitagliptin, sitagliptin and metformin, or sitagliptin and amitriptyline attenuate streptozotocin-nicotinamide induced diabetic neuropathy in rats. J Biomed Res 2012;26(3):200-10.

Davidson EP, Coppey LJ, Dake B, and Yorek MA. Treatment of Streptozotocin-Induced Diabetic Rats with Alogliptin: Effect on Vascular and Neural Complications. Exp Diabetes Res. 2011: 1- 7.

Király K, Kozsurek M, Lukácsi E, Barta B, Alpár A, Balázsa T, et al. Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropathic pain. Sci Reports. 2018;8:3490.

Balogha M, Vargaa BK, Karádia DA, Ribaa P, Puskárb Z, Kozsurekb M, et al. Similarity and dissimilarity in antinociceptive effects of dipeptidyl-peptidase 4 inhibitors, Diprotin A and vildagliptin in rat inflammatory pain models following spinal administration. Brain Res Bulletin. 2019;147:78-85.

Kumar CU, Pokuri VK, Pingali U. Evaluation of the Analgesic Activity of Standardized Aqueous Extract of Terminalia chebula in Healthy Human Participants Using Hot Air Pain Model. J Clin Diagnostic Res. 2015;9(5):1-4.

Prabhavathi K, Chandra USJ, Soanker R, Rani PU. A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model. Indian J Pharmacol. 2014;46(5):475.

Nalini P, Manjunath NK, Reddy KSK, Usharani P. Evaluation of the analgesic activity of standardized aqueous extract of Withania somnifera in healthy human volunteers using hot air pain model. Res J Life Sci. 2013;1(2):1-6.

Reddy KSK, Naidu MUR, Usha RP, Rao TRK. A simple thermal pain model for the evaluation of analgesic activity in healthy subjects. J Anaesth Clin Pharmacol. 2012;28:214-20.