Intravenous (IV) injection is one of the most common routes for delivering medications, fluids, and anesthetic agents in clinical practice. While generally safe and efficient, IV injections are often associated with discomfort or pain at the site of administration. The severity of this pain can range from mild stinging to intense burning sensations, depending on the drug, concentration, and infusion rate. The mechanism behind IV injection pain is largely linked to irritation of the endothelium of the vein receiving the medication.
The primary mechanism of pain during IV injection is the activation of nociceptors (specialized sensory nerve endings that detect noxious stimuli). These nociceptors, located within the vascular endothelium and surrounding tissues, respond to chemical, thermal, and mechanical signals. When certain drugs enter the bloodstream, they can directly stimulate these nerve endings or trigger the release of mediators that enhance pain signaling. The impulses are transmitted via peripheral nerves to the spinal cord and then to higher brain centers, where the sensation is perceived as pain or burning 1,2.
One of the most significant contributors to IV injection pain is the chemical composition of the injected solution. Drugs with extremes of pH or high osmolarity can irritate the vascular endothelium. For example, solutions that are strongly acidic (e.g., some antibiotics) or alkaline (e.g., phenytoin) disrupt the local chemical environment, causing endothelial irritation and direct activation of nociceptors. Hyperosmolar solutions draw water out of endothelial cells, leading to cell shrinkage and tissue injury, which also provoke painful sensations 3–5.
Certain medications are particularly notorious for causing injection pain. For instance, propofol, a commonly used anesthetic, produces pain in a large proportion of patients during injection. This is partly attributed to the drug’s lipid solvent, which activates the kallikrein-kinin system and releases bradykinin, a potent inflammatory mediator that sensitizes nerve endings. Similarly, antibiotics such as vancomycin and some chemotherapeutic agents can cause endothelial damage, leading to local pain and inflammation. Even non-irritant drugs can trigger pain when injected rapidly or in large volumes 6–9.
Apart from chemical properties, mechanical aspects of IV administration may also produce injection pain. Rapid injection increases intraluminal pressure, causing stretching of the vein and activation of mechanoreceptors that contribute to discomfort. In addition, the temperature of the injected solution can influence pain. Cold solutions tend to cause more vasoconstriction and discomfort compared to room-temperature or warmed solutions 10,11.
Another important mechanism of IV injection pain involves the release of inflammatory mediators at the site of injection. Agents that irritate the endothelium can cause localized inflammation, releasing histamine, prostaglandins, and kinins. These substances lower the threshold of nociceptor activation, amplifying pain perception. Repeated or high-dose injections may even damage the endothelium, increasing vascular permeability and contributing to phlebitis, which is characterized by persistent pain, swelling, and redness 12,13.
Pain during IV injection is a multifactorial phenomenon involving direct nociceptor activation, chemical irritation, osmolarity changes, inflammatory mediator release, and mechanical or thermal factors. By minimizing injection pain, healthcare providers can improve the overall patient experience and adherence to treatment.
References
1. Chen, J. (Steven), Kandle, P. F., Murray, I. V., Fitzgerald, L. A. & Sehdev, J. S. Physiology, Pain. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
2. Steeds, C. E. The anatomy and physiology of pain. Surgery (Oxford) 34, 55–59 (2016). DOI: 10.1016/j.mpsur.2015.11.005
3. Manrique-Rodríguez, S. et al. Standardization and Chemical Characterization of Intravenous Therapy in Adult Patients: A Step Further in Medication Safety. Drugs R D 21, 39–64 (2021). DOI: 10.1007/s40268-020-00329-w
4. Eichenbaum, G. et al. Methods to evaluate and improve the injection site tolerability of intravenous formulations prior to first-in-human testing. Journal of Pharmacological and Toxicological Methods 68, 394–406 (2013). DOI: 10.1016/j.vascn.2013.08.002
5. Ballesteros-Peña, S., Fernández-Aedo, I., Vallejo-De la Hoz, G., Tønnesen, J. & Miguelez, C. Identification of potentially irritating intravenous medications. Enferm Intensiva (Engl Ed) 33, 132–140 (2022). DOI: 10.1016/j.enfie.2021.05.003
6. Drouet, M. et al. Influence of Vancomycin Infusion Methods on Endothelial Cell Toxicity. Antimicrob Agents Chemother 59, 930–934 (2015). DOI: 10.1128/AAC.03694-14
7. Drouet, M. et al. Endothelial Cell Toxicity of Vancomycin Infusion Combined with Other Antibiotics. Antimicrobial Agents and Chemotherapy (2015). DOI:10.1128/aac.00612-15.
8. Kang, H.-J. et al. Clinical factors affecting the pain on injection of propofol. Korean J Anesthesiol 58, 239–243 (2010). DOI: 10.4097/kjae.2010.58.3.239
9. Desousa, K. A. Pain on propofol injection: Causes and remedies. Indian J Pharmacol 48, 617–623 (2016). DOI: 10.4103/0253-7613.194845
10. Paul, D. L., Logan, M. R. & Wildsmith, J. a. W. The effects of injected solution temperature on intravenous regional anaesthesia. Anaesthesia 43, 362–364 (1988). DOI: 10.1111/j.1365-2044.1988.tb09013.x
11. Zijlstra, E., Jahnke, J., Fischer, A., Kapitza, C. & Forst, T. Impact of Injection Speed, Volume, and Site on Pain Sensation. J Diabetes Sci Technol 12, 163–168 (2017). DOI: 10.1177/1932296817735121
12. St Clair-Jones, A., Prignano, F., Goncalves, J., Paul, M. & Sewerin, P. Understanding and Minimising Injection-Site Pain Following Subcutaneous Administration of Biologics: A Narrative Review. Rheumatol Ther 7, 741–757 (2020). DOI: 10.1007/s40744-020-00245-0
13. Chabot, K., Lavoie, M.-E., Bastard, J.-P. & Rabasa-Lhoret, R. Intravenous catheters induce a local inflammatory response. Cytokine 111, 470–474 (2018). DOI: 10.1016/j.cyto.2018.05.034