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Ketamine applications beyond anesthesia – A literature review

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Abstract

Ketamine's clinical use began in the 1970s. Physicians benefited from its safety and ability to induce short-term anesthesia and analgesia. The psychodysleptic effects caused by the drug called its further clinical use into question. Despite these unpleasant effects, ketamine is still applied in veterinary medicine, field medicine, and specialist anesthesia. Recent intensive research brought into light new possible applications of this drug. It began to be used in acute, chronic and cancer pain management. Most interesting reports come from research on the antidepressive and antisuicidal properties of ketamine giving hope for the creation of an effective treatment for major depressive disorder. Other reports highlight the possible use of ketamine in treating addiction, asthma and preventing cancer growth. Besides clinical use, the drug is also applied to in animal model of schizophrenia. It seems that nowadays, with numerous possible applications, the use of ketamine has returned; to its former glory. Nevertheless, the drug must be used with caution because still the mechanisms by which it executes its functions and long-term effects of its use are not fully known. This review aims to discuss the well-known and new promising applications of ketamine.

Introduction

After the discovery of anesthesia, in the 19th century, a quest for safe, efficient and short-acting anesthetics commenced (Baillie, 1965). One of the achievements on this path was a novel chemical organic Grignard reaction which led to the synthesis of phencyclidine (PCP) in 1956 (Maddox, 1965). PCP was a very safe anesthetic in humans but it also produced a state of prolonged delirium and sensory deprivation (Greifenstein, 1958). Thus, PCP began to be used as a drug model of schizophrenia (Luby et al., 1962) and the search for a short-acting derivative continued. The quest ended with the synthesis of CI-581, commonly known as ketamine, which also produced anesthesia but its effects where shorter (McCarthy et al., 1965; Domino, 2010). Ketamine was first used in humans in 1964 when it was administrated to 20 volunteer prisoners of the State Prison of Southern Michigan at Jackson, USA (Domino et al., 1965). Depending on the dose, the drug produced both full anesthesia and profound analgesia and an increase in blood pressure with no clinically significant respiratory depression. It had no effect on liver or kidney function and blood count (Domino et al., 1965). Due to ketamine's fast onset of action and the fact that it did not produce respiratory depression making it relatively safe (Corssen et al., 1965), it was used as a field anesthetic during the Vietnam War (Domino, 2010).

The most significant undesirable effect of ketamine is its psychological effects. Drug administration can cause very realistic hallucinations, dream-like experiences or mood changes. Usually, these effects would wear off within 1–2 h (Domino et al., 1965). Since ketamine synthesis, effects caused by these types of drugs were termed “dissociative anesthesia”. Due to its fast onset, a short period of action and hallucinogenic properties, ketamine has become a recreational drug of abuse. In subanesthetic doses, the drug produces hallucinations, distortion of time and space and mild dissociative effects. Recreational users describe it as a “melting into the surrounding” or an “out of body experience”. At higher doses, the drug can cause severe dissociative effects where people experience a complete detachment from reality (Curran and Morgan, 2000). First reports of ketamine recreational use appeared in the 1960s (Siegel, 1978) and the drug reached its peak in popularity in the 1990s when it was a common component of ecstasy tablets in Europe (Dalgarno and Shewan, 1996). To this day ketamine remains a popular drug of choice among young people of Hong-Kong (Joe-Laidler and Hunt, 2008).

Nowadays ketamine's most common clinical application is veterinary medicine. Due to its easy intramuscular administration route and because it does not depress respiratory function, ketamine has been used as a sedative and anesthetic in non-human primates, many zoological and exotic animals, birds and reptiles since the early seventies (Green et al., 1981). It is often applied in a combination with Xylazine, an adrenergic receptor agonist and can be used to aid anesthesia with inhalatory agents and to treat postoperative pain in non-human animals (Green et al., 1981; Wagner et al., 2002; Pöppel et al., 2015). In humans, its use as a general anesthetic has been minimized because of its psychological effects. However, Ketamine remains an anesthetic in special cases: in hemodynamically compromised emergency patients, such as patients in septic shock (Morris et al., 2009) and in adult and pediatric burn victims (Bayat et al., 2010; Zor et al., 2010; Reid et al., 2011; Norambuena et al., 2013; Kurdi et al., 2014). Ketamine is also applied in pain management (Curran and Morgan, 2000). The drug can be utilized as a model to study memory impairments and psychosis (Newcomer et al., 1999). In recent years the application of ketamine in treating depression (Serafini et al., 2014; Grady et al., 2017) as well as heroin and alcohol addiction (Krupitsky et al., 2002; 2007; Jovaisa et al., 2006; Wong et al., 2015) has been extensively studied. Ketamine's application in the management of acute, chronic and cancer pain is also being intensively researched (Kurdi et al., 2014). This review article aims to describe the wide range of ketamine applications.

Section snippets

Chemistry

Ketamine is a derivative of phencyclidine. It is a water-soluble aryl-cyclo-alkylamine with a molecular mass of 238 g/mol (Mion and Villevieille, 2013). Ketamine occurs in two enantiomers (S)-(+) and (R)-(-)-2-(2-chlorophenyl)-2-(methylamino) cyclohexanone (Morgan and Curran, 2012). Ketamine drugs such as Ketalar® are racemic mixtures of both enantiomers. The S(+) enantiomer is more potent and available as Ketanesth® in Europe (Mion and Villevieille, 2013). In 2019 the FDA has approved a nasal

Ketamine applications

In the following sections, various applications of ketamine are described (summarized in Fig. 2). A summary of example trials on ketamine's non-canonical functions is presented in Table 1.

Ketamine in asthma treatment

Ketamine works also as an airway relaxant and bronchodilator (White and Elig, 2013). Thanks to these properties, attempts were made to use ketamine for the treatment of asthma exacerbations (Sarma, 1992; Denmark et al., 2006; Shlamovitz and Hawthorne, 2011; Hendaus et al., 2016). It has been shown that IV administration of ketamine to children and adults suffering from an acute attack of asthma can prevent the need for intubation (Sarma, 1992; Denmark et al., 2006). The literature reports are

Conclusions and discussion

Ketamine has a wide range of applications. Its anesthetic properties are well established and continue to be used in some clinical settings. The use of ketamine in burn victims and in patients that are hemodynamically unstable remains of importance. Recent years, however, have brought the substance under the spotlight again due to its non-canonical uses. These fall on two interesting paths – one related to its psychological effects and another one independent of them.

In the areas related to

Conflicts of interest

Authors declare no conflicts of interest.

Authors contributions

AN wrote most of the manuscript and prepared the table, MB provided essential revisions, wrote sections of the manuscript and prepared the figures.

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