The myth and mending of ketamine


The origins of ketamineKetamine, a chemical derivative of phencyclidine (PCP), was first synthesized by Calvin Lee Stevens, Professor of organic chemistry at Wayne State University. Initially evaluated under the clinical number CI-581, the pharmacological actions were tested on volunteers from the population of Jackson Prison, Michigan in 1964. It was shown to be an effective analgesic and anaesthetic agent that gave patients a feeling of being ‘disconnected’ from the environment. The term ‘dissociative anaesthetic’ was coined by Toni Domino, the wife of one of the lead researchers, to describe the clinical effects of the drug (Domino, 2010).For many years, the mechanism of action of ketamine has been thought to be mainly due to the non-competitive antagonism of N-methyl-d-aspartate glutamate (NMDA) receptors. Glutamate is a major excitatory transmitter in the central nervous system—antagonizing the receptor leads to a decrease in neuronal activity and therefore anaesthesia.However, this is not the whole story. Ketamine appears to have several different sites of action and has been reported to interact with many systems such as opioid, monoamine, cholinergic, purinergic and adenosine receptors, as well as having local anaesthetic effects(White et al, 1982; Persson, 2010).‘Although ketamine is currently successfully used for analgesia in emergency medicine and the developing world, it is still unfairly demonized in some circles’The racemic mixture of ketamine, containing equal amounts of two ketamine enantiomers, S (+) and R (−), was approved for general clinical use in 1970 (White et al, 1982). During the past 41 years, the appropriate use of ketamine has divided opinion, and some controversial beliefs still muddy the waters of debate.

Ketamine [2-(O-chlorophenyl)-2-methylamino cyclohexanone] is a widely misunderstood drug. In approximately 50 years since it was developed, it has flitted in and out of popularity. Although ketamine is successfully used for analgesia in emergency medicine and the developing world, it is still unfairly demonized in some circles. With the continued evolution of differing operational models within prehospital care, we should be attempting to dispel some of the myths surrounding ketamine and highlight reasons why it may be a safe and effective option within this context.

The origins of ketamine

Ketamine, a chemical derivative of phencyclidine (PCP), was first synthesized by Calvin Lee Stevens, Professor of organic chemistry at Wayne State University. Initially evaluated under the clinical number CI-581, the pharmacological actions were tested on volunteers from the population of Jackson Prison, Michigan in 1964. It was shown to be an effective analgesic and anaesthetic agent that gave patients a feeling of being ‘disconnected’ from the environment. The term ‘dissociative anaesthetic’ was coined by Toni Domino, the wife of one of the lead researchers, to describe the clinical effects of the drug (Domino, 2010).

For many years, the mechanism of action of ketamine has been thought to be mainly due to the non-competitive antagonism of N-methyl-d-aspartate glutamate (NMDA) receptors. Glutamate is a major excitatory transmitter in the central nervous system—antagonizing the receptor leads to a decrease in neuronal activity and therefore anaesthesia.

However, this is not the whole story. Ketamine appears to have several different sites of action and has been reported to interact with many systems such as opioid, monoamine, cholinergic, purinergic and adenosine receptors, as well as having local anaesthetic effects(White et al, 1982; Persson, 2010).

‘Although ketamine is currently successfully used for analgesia in emergency medicine and the developing world, it is still unfairly demonized in some circles’

The racemic mixture of ketamine, containing equal amounts of two ketamine enantiomers, S (+) and R (−), was approved for general clinical use in 1970 (White et al, 1982). During the past 41 years, the appropriate use of ketamine has divided opinion, and some controversial beliefs still muddy the waters of debate.

Who should use ketamine?

Ketamine's product licence states that it is an intravenous general anaesthetic agent. This has led to the argument that only trained anaesthetists should use it. However, as Green and Krauss (2000) explain, this is only a question of semantics:

‘Any attempt to lump ketamine in the same category as anaesthetics is simply not evidence-based, and suggests an incomplete understanding of the distinct mechanism and effects of this drug.’

Ketamine is widely and safely used in the developing world and in combat situations where anaesthetists and appropriate monitoring are not always available (Bonanno, 2002; Guldner et al, 2006). It does not produce significant respiratory depression and airway reflexes are usually maintained (White et al, 1982; Green and Kraus, 2000). This means that the airway skills and competencies required to work with ketamine in the prehospital and emergency department context do not necessarily require specialist anaesthetic training.

Emergence reactions

Another commonly voiced concern surrounding ketamine is the possibility of ‘emergence reactions’ as patients recover from the dissociated state. These have been described as vivid dreaming, floating sensations, dizziness and blurred vision (White et al, 1982), and have often been cited as a reason to avoid ketamine in adults.

However, many reports have supported a low incidence of unpleasant adult emergence reactions (Porter, 2004; Svenson and Abernathy, 2007; Bredmose et al, 2009), and those that have found an increased incidence of neuropsychological effects (Galinski et al, 2007) reported them as minimal and fleeting, without the need for active treatment.

This suggests emergence reactions may be less of a clinical problem than previously thought, particularly in the prehospital and emergency medicine setting where it is less likely that a patient anaesthetized with ketamine would be allowed to wake in an uncontrolled environment.

Raising intracranial pressure

Historically, the use of ketamine in patients with an altered level of consciousness due to intracranial pathology was questioned, due to the potential for raising intracranial pressure (ICP). However, subsequent research has shown that intravenous doses of 1.5, 3 and 5 mg/kg failed to raise ICP (Albanese et al, 1997). Ketamine may also have a direct neuroprotective role (Marcoux et al, 1988; Hoffman et al, 1992) and use in head injury in previous prehospital care studies has not caused adverse reaction (Porter, 2004; Svenson and Abernathy, 2007; Bredmose et al, 2009; Jennings et al, 2011).

Risks and benefits

As with everything else in medicine, there is always a balance between risks and benefits, and failure to use ketamine in an agitated or combative patient with a reduced level of consciousness may present more risk to both patient and clinician than any risk directly ascribable to ketamine itself.

Adequate treatment of pain in trauma is of vital importance. Not only is it of humanitarian value but it also reduces morbidity, improves outcomes, and reduces the incidence of post traumatic stress disorder (Davidson et al, 2005).

Successful pain control begins at the prehospital phase. It is essential that personnel are equipped with the skills and medications that will allow them to achieve this safely and effectively for differing clinical scenarios. This is especially important in patients where pain is mediated via A-delta nerve fibres (e.g. musculoskeletal and skin), as this site specific pain is less influenced at a spinal level by opioid analgesia. Relying on supra-spinal effects of opioids in these patients can lead to inadequate analgesia with greater side-effects. Pragmatically, this includes most prehospital pain, with the exception being due to acute coronary syndromes.

Ketamine is a valuable addition to the prehospital armamentarium, either alone as a potent analgesic, or part of a balanced analgesia regime where it has an opioid-sparing effect (Galinski et al, 2007). It can be administered predictably intravenously (IV) or intra-muscularly (IM), and produces profound analgesia in doses well below that required to produce anaesthesia (White et al, 1982; Guldner et al, 2006). Intravenously, analgesia is present at 0.05-0.2 mg/kg and can be titrated to effect with further boluses, while anaesthesia is achievable at 2 mg/kg. Intramuscularly, analgesia is attained at 0.4 mg/kg and anaesthesia at 10 mg/kg.

Conclusions

This brief description of the less known benefits of ketamine compared with the more widely perceived adverse effects will hopefully encourage a greater use of this agent within prehospital and emergency medical and trauma systems. It is stable at room temperature and does not require specialist storage conditions (Porter, 2004).

A recent review has found it a safe and effective analgesic that does not cause increased incidence or severity of side-effects in comparison with other analgesics (Jennings et al, 2011). It has been shown to be to be safe in the hands of non-anaesthetists (Porter 2004; Jennings et al, 2011) and could be used by suitably trained and supported prehospital practitioners.

It is important that the myth and mystery surrounding ketamine is dispelled allowing it to be used appropriately by prehospital providers with the correct skill-sets and competencies (technical and nontechnical), regardless of their parent discipline—helping to achieve provision of safe, reliable and sustainable operational models to provide ‘the best for the most’ with regards to patient care.

Delays in the introduction of this agent and therefore the development of ‘fit-for-purpose’ modern models, should be addressed in an honest and transparent manner within appropriate forums, whether they are political, clinical or logistic.

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