Abstract:
Ketamine is a dissociative anesthetic agent, with excellent analgesic properties and a favorable safety profile. Although it acts predominantly through NMDA receptor antagonism, numerous other molecular targets have been characterized, rendering anti-inflammatory, anti-depressant, and thus expanding its scope for new clinical applications. The noticeable safety of ketamine in children enables its widespread use in pediatric oncology, chiefly for procedural sedation. Its value for chronic pain management in children with cancer is being increasingly recognized but requires more evidence. The topical use of ketamine is largely in investigational stages.. Rational medical use of ketamine is largely free from significant long-term neurological side effects but may have some troublesome short-term effects such as vomiting, palpitations, urinary retention, and hallucinations. This review will provide a brief account of the pharmacology of ketamine and primarily focus on the relevant aspects of ketamine in pediatric oncology.
Keywords: Ketamine; Oncology; Chronic pain; Sedation; Mucositis; Children
INTRODUCTION
The history of ketamine began almost seven decades back when the search for an ideal anesthetic and analgesic agent in the 1950s led to the discovery of a cyclohexylamine called Phencyclidine (PCP), also marketed as Sernyl.1 The advantages of PCP over other sedatives such as opioids were that it did not depress the cardiovascular and respiratory functions, nor did it impair the laryngeal and pharyngeal reflexes. These advantages, together with its potent anesthesia without a total loss of consciousness (later termed dissociative anesthesia) seemed promising. However, a major limiting adverse effect was the occurrence of psychotic reactions, including hallucinations lasting several hours, even after a single dose.2Additionally, the abuse potential of PCP was increasingly recognized. Thus, the initial excitement for PCP as a human anesthetic waned. Further research into similar compounds entailed the development of a compound in 1962 with a ketone bond together with an amine, hence named ketamine. This chemical had similar advantages as PCP, such as excellent anesthesia, hemodynamic stability, and preservation of protective reflexes, but with a shorter duration of action and lesser neuropsychiatric adverse effects.3 By 1970, ketamine was approved for human use. It was not until a decade later that the principal sites of its action, the NMDA receptors, were discovered.4 Another crucial observation was that ketamine, in sub-anesthetic doses, produces excellent analgesia, and was largely devoid of the troublesome psycho-behavioral adverse effects seen at higher doses. Since then, ketamine has been extensively studied, and a wide variety of therapeutic effects (anesthetic, analgesic, anti-inflammatory, anti-depressant) have been explored and their mechanisms characterized. Even though its role as an anesthetic has dwindled in the last three decades, its benefits in other domains remain of utmost utility, especially concerning analgesia in children, a population in which ketamine has proved to be noticeably safe and effective. The role of ketamine in acute severe asthma and refractory status epilepticus is also well-described. This review will provide a brief account of the pharmacology of ketamine and primarily focus on the relevant aspects of ketamine in pediatric oncology.
PHARMACOLOGY (Mechanisms of action, pharmacokinetics, routes of administration)
2.1 Mechanisms of action (MOA)
Ketamine has a use-dependent non-competitive NMDA receptor-channel blocking activity, wherein it binds the PCP site of the channel in the open activated state and reduces mean channel opening time. It has also been shown to bind to a second site on the membrane which, through an allosteric mechanism, causes a decrease in the frequency of the channel opening.5 The principal site of action of ketamine administered in anesthetic doses is the limbic system, manifesting as an increased uptake seen in nuclear studies. However, in sub-anesthetic doses, the activity in these regions is interestingly decreased.6,7 This coupled with the observation that low concentrations of ketamine act predominantly by the allosteric mechanism rather than by blocking the open NMDA channel, likely explain the differential effects of ketamine at different doses (anesthesia vs analgesia).8
Besides being effective at a dose much lower than that used for anesthetic effect, the efficacy of ketamine as an analgesic has also been noted to last even after the drug has cleared from the system. This is thought to be mediated by its sustained action on the glutaminergic neurons, which in turn causes an increase in structural synaptic connectivity.9 An interesting mechanism for relief in chronic pain is its desirable effect on pain memory and the desensitization of central pain pathways, as well as that on the motivational affective aspects of pain.10
Several other mechanisms of action have been proposed for the analgesic effect of ketamine based mostly on in-vitro studies, including dopamine D2 antagonism, 5-HT2 serotonin receptor agonism, HCN1 channels, calcium and sodium channels, and cholinergic transmission.11,12,13,14 These findings suggest that instead of a specific NMDA action, ketamine possibly has a multipronged role in modulating neural functions like pain, wakefulness, and mood.
Anti-inflammatory actions: Emerging evidence shows that ketamine also exerts an anti-inflammatory effect. Several studies, including both in vitro and in vivo, have demonstrated a reduction in blood levels of TNF-alpha, iNOS, IL-6, and C-reactive protein (CRP). This effect is likely mediated by inhibition of the NF-ĸB pathway, thereby impeding the pro-inflammatory cytokine response.15,16,17 Another possible mechanism could be the inhibition of inflammation-induced nitric oxide production.18,19 These effects may partly be responsible for the beneficial effects of ketamine in inflammatory and traumatic pain, such as that seen post-operatively.20However, a concrete clinical benefit of ketamine based on its anti-inflammatory actions is yet to be demonstrated, and this effect is likely at best a minor contributor to the overall benefit of ketamine as an analgesic. Additionally, a few animal model studies suggest a neuroprotective action owing to its NMDA antagonistic effects, but this has not been definitively replicated in humans yet.21,22
Local effects: NMDA receptors are present not only in the central nervous system (CNS) but also in peripheral sensory pathways. All motor and sensory axons are equipped with NMDA receptors. NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors are up-regulated on the axons as a reaction to inflammation.23 These findings support the rationale for treating neuropathic and inflammatory pain with topical ketamine to modulate NMDA, AMPA, and kainate receptors and subsequently downregulating the peripheral mechanisms contributing to neuropathic and inflammatory pain. Some other actions, particularly blockade of sodium channels, could contribute to its efficacy following local peripheral administration where tissue levels are likely to be higher than are attained with systemic administration.24 Ketamine has local anesthetic properties at high doses which have been compared with lignocaine and procaine, although with lesser potency.25 Indeed, ketamine has been widely studied as a topical agent for reducing post-tonsillectomy pain in children, including nebulized and oral rinse forms.26