Introductory Chapter: Is Ketamine the New Panacea of the 21^st Century?

1. Introduction

Ketamine is an old drug with bewildering uses. Although it was initially introduced in anesthesia, its use has spread to many areas, primarily due to its properties in the pain control and antidepressant domains.

It was first described as a drug with cataleptic, analgesic, and anesthetic action without hypnosis [1]. But its adverse effects, especially in terms of hallucinations and the availability of other anesthetics, made ketamine a controversial drug whose use was almost limited to disasters, the military, and third world countries. Nevertheless, it is still on the WHO Model List of Essential Medicines-22nd List.

But the last word is not said yet. On the contrary, new potential uses are being published that broaden the horizon. Of particular interest is to realize that the two different optical isomers of this drug can have differential actions and be used for various other therapeutic purposes in different nosological conditions. Right now, ketamine research is experiencing a resurgence. The better chemical and pharmacological knowledge, and the better control over its administration, are expected to return ketamine to a prominent place in the pharmacopeia of anesthesia.

The synthesis of ketamine resulted from an investigation on phencyclidine (PCP) in the 1950s, which was considered unsuitable for human anesthesia due to severe excitatory effects. Clavin Stevens synthesized in 1962 a related compound, a ketone plus an amine, which was called ketamine [2]. It has been in clinical use since 1970. In the next 10 years, studies revealed that it is a racemic mixture comprising equal parts of two optical isomers of the 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone ketamine: S(+) ketamine or esketamine and R(−) ketamine or arketamine, with differential effects. At the same time, some drugs were proposed to limit emergence excitement, such as chlorpromazine, diazepam, or droperidol [3, 4, 5]. Although physicians initially introduced it in the anesthetic armamentarium and later almost abandoned it in favor of other anesthetics with better profiles, many more applications are returning ketamine to the present day.

2. Pharmacokinetics

Its pharmacological action is achieved through the N-methyl-d-aspartate (NMDA), opioid, muscarinic, and several voltage-gated receptors. Its anesthetic and analgesic properties are due to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors.

Esketamine (S-Ketamine) is almost four times more potent than arketamine (R-Ketamine) to induce anesthesia and analgesia due to the higher affinity of the former for the NMDA receptors [6, 7], but also more prone to cause side effects [6].

Because it is both water and lipid-soluble, it can be administered to most routes (oral, sublingual, transmucosal, intravenous, intramuscular, subcutaneous, intranasal, and rectal) [8], providing an excellent distribution in the whole body [9].

It induces bronchodilatation and sympathetic nervous and cardiovascular system stimulation [9], two characteristics that give ketamine an interesting role in shock and anesthesia-related cardiovascular depression.

Ketamine is a well-tolerated drug in the short term, but it induces an increase in salivation, arterial and intracranial pressure [10, 11], cardiorespiratory [10, 12], neuropsychiatric, dissociative, and psycho-mimetic effects with delirium [7, 10, 11, 13], and psychodysleptic, cognitive, and peripheral side effects [14, 15]. The most common are the psycho-mimetic side effects [9, 11]. Nevertheless, in the long-term, it can induce neurocognitive and urologic toxicity [7, 16] and has the potential of abuse [13], same as its predecessor, phencyclidine (PCP). Therefore, experts recommend not to administer this drug to patients suffering from arterial hypertension or coronary artery disease [17].

It is metabolized in the liver primarily to norketamine, which is an active metabolite [18]. This characteristic makes it a good option when considering the oral route (although this is not approved). Other metabolites are dehydronorketamine, hydroxyketamine, and hydroxynorketamine [19], all of which, but particularly the last one, has antidepressant effects [20].

3. Clinical uses

Today it is relatively simple to control its side effects. Hence, its clinical uses have escalated from only anesthesia, to its use in the pain clinic, neurology, psychiatry, palliative care, and others.

It is well known that it induces dissociative anesthesia, which means that although the sensory inputs reach the cortical receiving areas, these inputs are not perceived at the association cortex. The lack of loss of consciousness together with the preservation of ventilation and cardiovascular stability made it a drug of choice in wars and disasters, and in third world countries.

Thus, it is useful for premedication, sedation, and induction and maintenance of general anesthesia, particularly esketamine.

Additionally, the analgesic action is present with plasma levels 10 times lower than those required for hypnotic purposes [18], which confers ketamine a high interest in acute and chronic pain treatment. Also, anti-inflammatory and even antidepressant properties have been described. Finally, at subanesthetic doses, this form of ketamine is helpful in postoperative analgesia and sedation [21].

It has excellent potential in trauma patients [22, 23, 24], even in children [2], hypovolemic or septic shock, and pulmonary diseases.

Its use in ICU patients is also increasing, usually combined with midazolam or propofol, and particularly in patients with sepsis or cardiovascular instability [25]. It also has excellent potential in short anesthetic procedures, particularly in pediatric patients [26] and endoscopic diagnostic procedures [27].

Because of its anti-hyperalgesic and anti-inflammatory properties, ketamine is currently used to treat acute and chronic pain [28]. It is gaining a role in acute pain treatment. In the postoperative period, it not only controls the pain [29, 30] but also improves patients’ mood and depression [31].

Moreover, patients suffering from chronic pain, particularly of oncologic origin [14, 32], may benefit from a treatment that includes ketamine, either used as a single drug or combined with others, or as a substitute when other medications are not well tolerated [9]. An additional bonus is that it can be administered orally, both in adults and children [8]. The effects of this drug on chronic pain patients might be due, at least in part, to the modulation of the effective aspects [33] and to the fact that it can help to fight depression in chronic pain patients [8].

Sub-anesthetic doses of ketamine have antidepressant action [12, 34, 35], particularly in major depressive and bipolar disorders [36, 37] and resistant depression [12, 38]. Its antidepressant action starts within 2 hours of administration, and this effect is sustained for about 7 days on average and reduces suicidal ideation [39, 40] and suicidal attempts [7, 8, 14]. It has also been recommended as an anesthetic agent in electroconvulsive therapy to treat chronic depressive disorders [12, 38, 41]. Although low doses of intranasal esketamine are very effective and approved by the FDA (March 5, 2019) [6, 7, 42] and Europe (December 19, 2019) [43], the intravenous route is more potent [44, 45]. The oral route, although not yet approved, has also been used [8, 38, 46]. However, other researchers have found that arketamine is more effective and has more lasting antidepressant effects [47], at least in animal models [36, 48], and fewer side effects [47].

A new whole area of research is being explored in Psychiatry. It has a potential application in treatment-resistant generalized anxiety and social anxiety disorders [49]. Lately, some have started to use ketamine successfully to treat posttraumatic stress disorder (PTSD) both from military and civilian origin [50].

Other uses are to treat alcohol abuse and drug addiction (like heroin and cocaine) [42], asthma [51], and even prevent cancer growth [14].

4. Ketamine side effects

As it happened with phencyclidine, which was finally placed on the Schedule I list of illegal drugs in the 1970s, ketamine use has also been associated with abuse, particularly among young people using this drug for recreational purposes and spiritual seekers seeking schizophrenia-like symptoms and mental dissociation (i.e., out-of-body experience) [47].

The long-term consequences of chronic high ketamine dose administration are unknown, although neuronal apoptosis has been seen in animal models, particularly in the neonatal and pediatric periods [18]. What is known is that frontal white matter changes with cognitive deterioration happen in chronic ketamine abusers [18]. However, at this moment, there is not that much experience concerning the chronic use in the clinical setting, as in clinical praxis it is restricted to chronic pain of neuropathic or oncogenic origin.

5. Benefits versus harm: the panacea effect

Although ketamine has been living a real genuine revival in the last 10 years, clear boundaries have not been established yet. The situation looks like the rediscovery of a hidden germ. We are now on an upward learning curve, same as with any new drug when it is used for several different clinical situation trying to explore the whole set of benefits and the most secluded of latent cons that could overcome those pros.

Even if not a panacea, perhaps will ketamine in this 21st century, more than 60 years after it was synthesized, reach its full clinical potential. It seems that the last century was not prepared for it.

6. Conclusion

Ketamine is a drug with many possible uses and abuses. Physicians need to know all its potential to use it for the patients’ best benefit but also be careful to avoid unwanted side effects. More research is needed to clearly establish boundaries on indications based on its clinical benefits.

Conflict of interest

The authors declare no conflict of interest.