Local anesthetics are crucial in clinical practice, being among the most utilized medications during invasive procedures, ranging from dental to major operations. However, their integration into regular clinical practice has been a prolonged and unanticipated journey. The history of local anesthetics can be traced back to coca leaves, which were used by the ancient Inca civilization in Peru (Calatayud & González, 2003). The anesthetic effects of these leaves, particularly the numbing of the tongue and lips, have been recognized for centuries (Calatayud & González, 2003). It was then in 1860 when the German chemist Albert Niemann isolated the active compound derived from these leaves and coined the name ‘cocaine’ (Niemann, 1860a; Niemann, 1860b). Subsequently, its molecular structure “C17H21NO4” was later determined by Wilhelm Lossen in 1865 (Lossen, 1865).

There have been numerous efforts to harness the potential of cocaine for use as a local anesthetic since its isolation. Thomas Moreno y Maïz, a Peruvian surgeon, discovered that cocaine induced numbness in rats, guinea pigs, and particularly in frogs when injected (Moreno, 1868). The anesthetic capabilities of cocaine were further reported by Russian physician Basil von Anrep in 1880 (Von Anrep, 1880), and ophthalmologist Carl Koller used cocaine as a local anesthetic during surgery in 1884 (Fink, 1985; Koller, 1884a; Koller, 1892). At the time, ophthalmologists typically refrained from using general anesthesia for cataract operation due to the significant post-operative nausea and vomiting it caused. Therefore, many cataract operations were conducted without any form of anesthesia (Leffler, Klebanov, Samara, & Grzybowski, 2020). Before introducing the use of cocaine in animal and human trials, Carl Koller initiated its use through “self-experimentation” on his oral mucosa (Koller, 1884b). This application of cocaine as an anesthetic rapidly gained international attention. Cocaine was being used globally in the developed world, specifically for cataract surgeries, within just a year of Koller's revelation (Tobe, Suto, & Saito, 2018).

The deleterious effects of cocaine became promptly apparent after its introduction in surgery, resulting in significant mortality due to addiction among both patients and medical professionals (Olch, 1975). William Stewart Halsted, who later became the father of modern American surgery, is also well-known as a cocaine addict when he was experimenting its role as a local anesthetic among the surgeon researchers, and he ended up being the sole survivor. It became clear that cocaine was not the ideal agent for local anesthesia, given its pronounced addictive potential, toxicity, propensity to induce allergic reactions, and limited duration of efficacy. These limitations of cocaine led to extensive pharmaceutical research for alternative topical anesthetics which resulted in Alfred Einhorn's development of procaine in 1904, providing a safer substitute for cocaine (Tobe et al., 2018). In 1943, lidocaine was developed by Nils Löfgren and Bengt Lundquist as a faster-acting and longer-lasting local anesthetic with reduced allergenic potential (Löfgren, 1948). The clinical utility of lidocaine was reported five years later by Torsten Gordh (Holmdahl, 1998), leading to a greater appreciation of the value of nerve block techniques, including epidural analgesia. Subsequently, several synthetic local anesthetics, such as bupivacaine (introduced in 1957), prilocaine (introduced in 1959), and ropivacaine (introduced in 1997), were developed and are commonly used in clinical practice currently (Ruetsch, Böni, & Borgeat, 2001).

Lidocaine has come to be used in various clinical settings as a local anesthetic through such a historical progression. On the other hand, the antitumor effects of lidocaine on cancer cells have recently been observed in vitro. Even more remarkably, recent literature suggests that the use of lidocaine may influence the survival of cancer patients. In this review, we will first outline the fundamental mechanism of lidocaine as a local anesthetic, the mechanisms of lidocaine's effect on cancer cells and in the tumor microenvironment, and the latest reports on its impact on the survival of cancer patients.