Investigation of Analgesic Effects of Venlafaxine, Atomoxetine and Trazodone Alone and in Combination in Acute Pain Models of the Rats

Abstract

Purpose: Poorly controlled pain is linked to several other undesirable outcomes. These outcomes are upsetting to patients, their families, and society as a whole. Although opioids and non-steroidal anti-inflammatory drugs are the cornerstone of the nociceptive pain treatment, the use of these drugs is restricted due to their side effects. Therefore, it is essential to develop new treatment alternatives for pain. Our study aimed to examine the pain relief effectiveness of Venlafaxine, Atomoxetine and Trazodone at 3 different doses alone, and in combination with each other in an acute pain model. Material and Methods: The analgesic effectiveness of Venlafaxine, Atomoxetine, and Trazodone at three different doses alone and in combination in an acute pain model in rats was examined using the hot plate and tail flick methods. Results: Venlafaxine and Trazodone, Venlafaxine showed dose-dependent analgesic effect when compared to the control. When Venlafaxine at dose of 2 mg/kg were combined with Atomoxetine at doses of 1, 3 and 6 mg/kg, the analgesic effects were significantly increased compared to these drugs alone. When Venlafaxine at dose of 2 mg/kg were combined with trazodone at doses of 4, 12 and 24 mg/kg, the analgesic effects were significantly increased compared to these drugs alone. Conclusion: All in all, our data suggest these combinations may offer a beneficial treatment option for acute pain in future.

Keywords

• Acute Pain
• Venlafaxine
• Atomoxetine
• Trazodone
• Hot Plate
• Tail Flick
• Analgesic Effect.

References

1. Barbaros, M.B., Can, Ö.D., Üçel, U.I., Yücel, N.T., DemirÖzkay, Ü., 2018. Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems. Mol. 2018, Vol. 23, Page 2072 23, 2072. https://doi.org/10.3390/MOLECULES23082072
2. Bonnefont, J., Chapuy, E., Clottes, E., Alloui, A., Eschalier, A., 2005. Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT. Pain 114, 482–490. https://doi.org/10.1016/J.PAIN.2005.01.019
3. Cegielska-Perun, K., Bujalska-Zadrozny, M., Makulska-Nowak, H.E., 2012. Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model. Pharmacol. Reports 64, 1267–1275. https://doi.org/10.1016/S1734-1140(12)70923-4
4. Chen, J. (Steven), Kandle, P.F., Murray, I., Fitzgerald, L.A., Sehdev, J.S., 2021. Physiology, Pain. StatPearls. Cortes-Altamirano, J.L., Olmos-Hernandez, A., Jaime, H.B., Carrillo-Mora, P., Bandala, C., Reyes-Long, S., Alfaro-Rodríguez, A., 2018. Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. Curr. Neuropharmacol. 16. https://doi.org/10.2174/1570159X15666170911121027
5. Demirkazik, A., Ozdemir, E., Arslan, G., Taskiran, A.S., Pelit, A., 2019. The effects of extremely low-frequency pulsed electromagnetic fields on analgesia in the nitric oxide pathway. Nitric Oxide - Biol. Chem. 92, 49–54. https://doi.org/10.1016/j.niox.2019.08.003
6. Fernández-Dueñas, V., Poveda, R., Fernández, A., Sánchez, S., Planas, E., Ciruela, F., 2011. Fentanyl–trazodone–paracetamol triple drug combination: Multimodal analgesia in a mouse model of visceral pain. Pharmacol. Biochem. Behav. 98, 331–336. https://doi.org/10.1016/J.PBB.2011.01.023
7. Florkowski, A., Gruszczyński, W., Gałecki, P., Zboralski, K., Kołodziejska, I., Mikołajczyk, I., 2005. [Trazodone and venlafaxine in treatment of depressive disorders]. Pol. Merkur. Lekarski 18, 556–559.
8. Fornasari, D., 2017. Pharmacotherapy for Neuropathic Pain: A Review. Pain Ther. 2017 61 6, 25–33. https://doi.org/10.1007/S40122-017-0091-4

9. Grothe, D.R., Scheckner, B., Albano, D., 2004. Treatment of Pain Syndromes with Venlafaxine. Pharmacother. J. Hum. Pharmacol. Drug Ther. 24, 621–629. https://doi.org/10.1592/PHCO.24.6.621.34748
10. Gültekin, H., Ahmedov, V., 2006. The Roles of the Opioidergic System and Nitric Oxide in the Analgesic Effect of Venlafaxine. YAKUGAKU ZASSHI 126, 117–121. https://doi.org/10.1248/YAKUSHI.126.117
11. Hajhashemi, V., Banafshe, H.R., Minaiyan, M., Mesdaghinia, A., Abed, A., 2014. Antinociceptive effects of venlafaxine in a rat model of peripheral neuropathy: Role of alpha2-adrenergic receptors. Eur. J. Pharmacol. 738, 230–236. https://doi.org/10.1016/J.EJPHAR.2014.04.046
12. Hart, F.D., Huskisson, E.C., 2012. Non-Steroidal Anti-Inflammatory Drugs. Drugs 1984 273 27, 232–255. https://doi.org/10.2165/00003495-198427030-00004
13. Jamison, R.N., Mao, J., 2015. Opioid Analgesics. Mayo Clin. Proc. https://doi.org/10.1016/j.mayocp.2015.04.010
14. Kanaan, S.A., Saadé, N.E., Haddad, J.J., Abdelnoor, A.M., Atweh, S.F., Jabbur, S.J., Safieh-Garabedian, B., 1996. Endotoxin-induced local inflammation and hyperalgesia in rats and mice: A new model for inflammatory pain. Pain 66, 373–379. https://doi.org/10.1016/0304-3959(96)03068-0
15. Khouzam, H.R., 2016. A review of trazodone use in psychiatric and medical conditions. http://dx.doi.org/10.1080/00325481.2017.1249265 129, 140–148. https://doi.org/10.1080/00325481.2017.1249265
16. Lussier, D., Huskey, A.G., Portenoy, R.K., 2004. Adjuvant Analgesics in Cancer Pain Management; Adjuvant Analgesics in Cancer Pain Management. Oncologist 9, 571–591. https://doi.org/10.1634/theoncologist.9-5-571
17. Marchand, F., Alloui, A., Chapuy, E., Jourdan, D., Pelissier, T., Ardid, D., Hernandez, A., Eschalier, A., 2003. Evidence for a monoamine mediated, opioid-independent, antihyperalgesic effect of venlafaxine, a non-tricyclic antidepressant, in a neurogenic pain model in rats. Pain 103, 229–235. https://doi.org/10.1016/S0304-3959(03)00168-4
18. Neugebauer, V., 2020. Serotonin—pain modulation. Handb. Behav. Neurosci. 31, 309–320. https://doi.org/10.1016/B978-0-444-64125-0.00017-7
19. Ozdemir, E., Demirkazik, A., Taskıran, A.S., Arslan, G., 2019. Effects of 5-HT1 and 5-HT2 Receptor Agonists on Electromagnetic Field-Induced Analgesia in Rats. Bioelectromagnetics 40, 319–330. https://doi.org/10.1002/BEM.22196
20. Ramabadran, K., Bansinath, M., Turndorf, H., Puig, M.M., 1989. The hyperalgesic effect of naloxone is attenuated in streptozotocin-diabetic mice. Psychopharmacology (Berl). 97, 169–174. https://doi.org/10.1007/BF00442244 Rummans, T.A., 1994. Nonopioid Agents for Treatment of Acute and Subacute Pain. Mayo Clin. Proc. 69, 481–490. https://doi.org/10.1016/S0025-6196(12)61648-6
21. Scotton, W.J., Hill, L.J., Williams, A.C., Barnes, N.M., 2019. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions: https://doi.org/10.1177/1178646919873925 12. https://doi.org/10.1177/1178646919873925
22. Shipton, E.A., Shipton, E.E., Shipton, A.J., 2018. A Review of the Opioid Epidemic: What Do We Do About It? Pain Ther. 2018 71 7, 23–36. https://doi.org/10.1007/S40122-018-0096-7
23. Sumpton, J.E., Moulin, D.E., 2001. Treatment of neuropathic pain with venlafaxine. Ann. Pharmacother. 35, 557–559. https://doi.org/10.1345/aph.10206
24. Tao, Z.-Y., Wang, P.-X., Wei, S.-Q., Traub, R.J., Li, J.-F., Cao, D.-Y., 2019. The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System. https://doi.org/10.1155/2019/1389296
25. Taylor, B.K., Westlund, K.N., 2017. The noradrenergic locus coeruleus as a chronic pain generator. J. Neurosci. Res. 95, 1336–1346. https://doi.org/10.1002/JNR.23956