Learning Objectives/Outcomes:After participating in this CME/CNE activity, the provider should be better able to:
1. Explain how ketamine was developed as an anesthetic agent.
2. Identify its use in ameliorating postoperative pain.
3. Evaluate the potential for treatment or exacerbation of posttraumatic stress disorder.
4. List the consensus guidelines for acute pain management.
Ketamine, in use since the 1970s as anesthesia and analgesia, has a long history and relatively safe profile for use in the operating room (OR), during procedures, and even in the battlefield. More recently, ketamine has gained a body of evidence about its potential for use in acute postoperative pain and chronic pain management, and in treating severe depression and posttraumatic stress disorder (PTSD). To give clinicians some history of this drug and its newer uses, this article reviews the evidence and emerging use of ketamine in patients with these disorders and as part of a multimodal approach to pain management.
The Old
Ketamine was first synthesized in 1962 by the late Calvin Stevens, PhD, at the Parke-Davis laboratories in Michigan. It is one of the cyclohexylamine compounds that also include phencyclidine. However, ketamine was the only drug of the group that was found to be clinically useful, as the other agents caused postoperative delirium and psychomimetic reactions.
Quickly Embraced for the OR and the Battlefield
In 1964, ketamine underwent its first human trial, with testing mainly in prisoners. The drug was originally promoted as a fast-acting general anesthetic, but illicit use developed quickly.1-4
Corrson and Domino termed the effects of ketamine "dissociative anesthesia" in 1966 to better describe the trance-like state of analgesia produced by the agent.5 US approval for use of ketamine as an anesthetic was confirmed in 1970.2,3 Because of its apparent safety-in that spontaneous respiration and blood pressure were maintained-ketamine was extensively used for surgical anesthesia during the Vietnam War and in subsequent military operations.6 The World Health Organization included the drug in its List of Essential Medicines, which identifies the most effective and safe medicines needed in a health system.7
Illicit Use Grows
However, during the 1980s and 1990s, new formulations of ketamine were developed and found their way into many subcultures, such as new-age spiritualists. Capsules, powder, crystals, tablets, and solutions, in addition to other injectable forms, were distributed. An increase in the social-recreational use of ketamine was linked to some dance-club cultures; initially, it was probably added as an adulterant.8 Whether or not they knew it, partygoers in the United Kingdom thought they may have been ingesting ketamine when it had been mixed with ecstasy (3,4-methylenedioxymethamphetamine, a euphoric stimulant and hallucinogen with a chemical relationship to the psychedelic drug mescaline).
Prevalence of illegal use has continued and may even be higher now than when the drug was first introduced. As a consequence, the federal government classified ketamine as a schedule III controlled substance in August 1999, creating more stringent controls.1
Chemical Properties
Based on the chemical makeup of ketamine, many uses for the agent have been proposed for several reasons. Glutamate is the major excitatory amino acid in the central nervous system. It plays a critical role in a variety of normal and abnormal physiologic processes, including neurodevelopmental and neurotrophic effects, neurocognitive functions, modulation of other neurotransmitter systems, and neurodegeneration including nerve cell damage and death. After release from nerve cells, glutamate binds to receptors and is removed by complex reuptake receptor systems that may be divided into subtypes according to molecular and pharmacologic properties.
The 2 main classes of glutamate receptors are "ionotropic" and "metabotropic." Ionotropic glutamate receptors are further divided into 3 groups: N-methyl-D-aspartate (NMDA), [alpha]-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate. Moreover, each group is further divided into subtypes. Metabotropic glutamate receptors are also classified into 3 groups, with 8 subtypes. Ketamine acts as a selective antagonist of the NMDA receptor, an ionotropic glutamate receptor.9
Ketamine is available in several formulations, including IV, intramuscular, oral, and intranasal. It was used initially as an induction agent for anesthesia at an IV dose of 1 to 2 mg/kg. This dose allows rapid loss of consciousness (45-60 seconds) while still maintaining spontaneous ventilation. Duration of action is about 10 to 20 minutes although time to full recovery may require an additional 60 to 90 minutes. If a continuous infusion (0.1-0.5 mg/min) is used in addition, emergence times are even longer.
The drug is metabolized by hepatic microsomal cytochrome p-450 enzymes with a primary metabolite of norketamine, which is about one-third as potent as the parent compound. Metabolites of norketamine are excreted by the kidneys. Ketamine has a high hepatic extraction ratio, which means that alterations of hepatic blood flow may delay clearance of the drug.10
Side Effects
Concerns about ketamine were based on the fact that, in these anesthetic doses, it has been shown to have serious adverse effects in 10% to 20% of patients during emergence, with reactions manifesting as hallucinations, delirium, and even attempts at suicide.11,12 These reactions may be lessened if the drug is given intramuscularly, but can still occur up to 24 hours postoperatively. The chance of nightmares occurring can be reduced by minimizing stimulation during recovery and pretreating with benzodiazepines, barbiturates, and propofol, or using a lower dose of ketamine.1,10
However, all of these ancillary agents potentially delay return to consciousness. Also, ketamine, again in anesthetic doses, increases blood pressure and heart rate, by the inhibition of the reuptake of serotonin, norepinephrine, and dopamine effects desirable in trauma patients but not in those with chronic hypertension.
Indeed, ketamine may be the drug of choice in severely injured people who are at risk for hypotension, a condition that may prove catastrophic for patients with major head injury.11,12
Related to this hypertensive effect, a 2011 clinical practice guideline outlined the use of ketamine as a dissociative sedative in emergency medicine.13 Peripheral arteriole resistance is increased, and therefore the amount of redistribution of hypothermia is reduced, maintaining core temperatures, especially in trauma victims.10
The drug has also been shown to have well-documented bronchodilator activity in patients with active bronchospasm and is the drug of choice in those circumstances. In low doses, ketamine may be used to treat persistent bronchospasm, especially in combination with midazolam, to provide sedation and analgesia for asthmatic patients. Tonic-clonic movements are reported at higher anesthetic doses in more than 10% of people.14
Traditionally, ketamine was considered contraindicated in patients with intracranial pathology because the drug may increase intracranial pressure), cerebral blood flow, and cerebral metabolic rate of oxygen use. More recent studies have suggested that ketamine may be beneficial to the injured brain through NMDA antagonism and by inhibition of spreading depolarization after acute injury (discussed further later).14,15
The New
Because drugs are able to bind to different glutamate receptor subtypes, they can then modulate glutamate function with varying physiologic and clinical effects, an effect first reported more than 50 years ago. As noted earlier, ketamine acts as a potent NMDA antagonist, which explains many of its effects in combating severe depression.16 Ketamine also binds to [mu]- and [sigma]-opioid receptors and may modulate dopamine transmission and potentiate serotonin 5-HT3 receptors.17
Studies of Ketamine as Fast-Acting Treatment of Depression
Although ketamine was found to have some antidepressant effects, it is only more recently that the benefits of these effects have been studied. It has been shown to act as a rapid-acting antidepressant in major depressive disorder, treatment-resistant depression (TRD), and bipolar depression.18-20 Moreover, it also seems to be effective in rapidly alleviating suicidal ideation, although the quality of evidence is somewhat lower.21,22 A recent small study indicated that ketamine at a dose of 0.5 mg/kg over 45 minutes had limited beneficial effects.23
Other researchers have shown that a single low, subanesthetic dose of ketamine at the same dose given intravenously can reverse depression within 4 hours, an effect that lasts for at least a week and in some cases is even longer, in sharp contrast to conventional antidepressants such as selective serotonin reuptake inhibitors and tricyclic antidepressants that require weeks for maximal effect.18 Also, the degree of alleviation of depression is more than double with ketamine than that seen with conventional agents.18 A recent review has described ketamine as the single most important advance in the treatment of depression in over 50 years, shifting the research from traditional antidepressants to NMDA receptor antagonists. It should be noted that ketamine has not been approved or marketed for use as an antidepressant and use for these purposes is off-label.24,25
There remains a lack of consensus on optimal dosing and the benefits of long-term therapy, in part because of the drug's potential for abuse.20,26 Also, the mechanism of effects of ketamine at lower doses is also not well understood, whether it is by acute block of NMDA receptors that modulate several downstream signaling pathways that, in turn, influence neurotransmitters in the limbic system or reuptake of brain-derived neurotrophic factor (BDNF), which can be measured by blood sampling, other effects of active metabolites, or some combination.27
A recent study has suggested that the dose be increased to 1 mg/kg over 40 minutes in patients with TRD.28 Although the researches described transient increases in blood pressure and dissociative symptoms, the dose was well-tolerated with satisfactory results in most cases. Other reports have demonstrated sustained success with up to 6 infusions in many patients with unipolar or bipolar depression.29
Potential for Ketamine in Treating PTSD
Yet other uses of ketamine have been expanded to explore efficacy or harm in the management of PTSD. A Canadian report has been developed to inform clinical practitioners on the treatment of patients with TRD or PTSD, aiming to provide evidence on the clinical benefits and harms and evidence-based guidelines on the off-label use of ketamine in various settings.30 Some promising results have been found in the studies involving the use of ketamine to treat the PTSD patient population.
Initially, some clinicians had concerns. Because of the side effects of hallucinations and the common use of ketamine as an anesthetic in battlefield medicine and other military operations since the 1970s, the question arose as to whether PTSD might be exacerbated in soldiers who had received the drug.31 However, at least one study in French soldiers has allayed those concerns.
In this study of 274 French military personnel in Afghanistan, 98 (36%) suffered from PTSD and 89 (32%) had received ketamine. In the PTSD group, 54 patients (55%) received ketamine versus 35 (20%) in the no-PTSD group (P < 0.001). The authors concluded that only acute stress and total number of surgical procedures were independently associated with the development of PTSD, and that ketamine administration was not a risk factor for the development of PTSD in the military trauma setting.31
Focusing on assessment of BDNF may be an appealing approach to further research, as that is the factor that promotes proliferation and survival of neurons. PTSD is commonly associated with a decrease in BDNF, and one of the actions of ketamine, as noted earlier, is to inhibit the hyperpolarization-activated cyclic nucleotide-gated channel 1 and regulate BDNF expression.32
Another approach to the management of patients with PTSD involved assessment of a plasma marker, D-serine (DSR). The study included an approach called Trauma Interventions using Mindfulness-Based Extinction and Reconsolidation (TIMBER), developed by one of the study's authors, Basant K. Pradhan, MD, of Cooper Medical School of Rowan University. After administration of a single subanesthetic dose of (R,S)-ketamine (an isomer) combined with mindfulness-based cognitive therapy (specifically, TIMBER), researchers obtained sustained response rates of 34.44 +/- 19.12 days.33 When compared with a placebo arm that also included TIMBER, response was restricted to 16.50 +/- 11.39 days. In this study, basal DSR levels positively correlated with the pretreatment severity of PTSD symptoms. Patients with a basal DSR level of 3.5 [mu]M or more displayed not only higher PTSD severity but also shorter duration of response, indicating that basal DSR levels may serve as a biomarker of the severity of PTSD symptoms and as a predictor of clinical response
The Newest
Ketamine's Role in Multimodal Pain Management
Postoperative pain remains of significant concern to patients and caregivers. To that end, clinicians have developed multimodal protocols, including preemptive analgesia, intraoperative medications, and postoperative infusions. There is much interest in when and how best to include ketamine in this multimodal approach; whether its use can help reduce or eliminate opioid analgesia in patients who might be at risk of opioid complications; and whether there is a role for ketamine in helping to reverse the nationwide rise in opioid-related deaths overall.
The increasing incidence of obesity, often with the complication of obstructive sleep apnea, has made physicians and nurses wary of using opioids because of the real risk of postoperative respiratory depression in these patients. Increasingly, ketamine, with its safer profile and ability to allow spontaneous respiration, has been added to the plans for pain management. By combining the analgesic properties of ketamine with the awareness that even low-dose administration can have significant effect, protocols have been developed to infuse ketamine intraoperatively to reduce postoperative pain while reducing the need for narcotics.
A systematic review and meta-analysis indicated that low-dose ketamine (<=0.5 mg/kg as an IV bolus or <=5 [mu]g/kg/min for perfusion) reduced postoperative morphine consumption and pain intensity without increasing the incidence of adverse effects.34 Moreover, in a study of patients undergoing spinal fusion, most of whom had received narcotics preoperatively, a low-dose ketamine infusion reduced opioid requirements for the first 24 hours after surgery in opioid-tolerant patients. The same effect was not found in opioid-naive patients.35
Applications have recently been extended outside the OR. Postanesthetic and intensive care nurses must also be aware that low-dose ketamine is increasingly being ordered, especially for patients at risk of sleep apnea and for amelioration of hyperanalgesia after intraoperative discontinuation of such agents as remifentanil.36,37
New Guidelines From 3 Medical Societies
In an attempt to try to identify questions surrounding the uses of ketamine and to formulate answers and conclusions that might still require further explanation, 3 societies-the American Society of Anesthesiologists, the American Society of Regional Anesthesia and Pain Management, and the American Academy of Pain Medicine-collaborated to write guidelines both for acute and chronic pain management.38,39 (See also News in Brief; Topics in Pain Management. 2018:34(2):12.)
The authors note that ketamine is an incredibly useful tool with a highly acceptable side effect profile, typically less than that of opioids, but that it is overshadowed by a misconception regarding adverse effects. Doses to manage acute perioperative pain are in the subanesthetic range and therefore have many fewer adverse reactions.
The guidelines drafted by these 3 societies for acute pain management pose 6 key questions and offer evidence-supported conclusions based on extensive literature review. The guidelines are intended for all practitioners in pain management, institutions, and third-party payers. The goals are to develop protocols, guide decision-making, and improve patient outcomes and safety.
In summary, the questions help to identify:
* Which patients with acute pain should be considered for ketamine therapy?
* What is the dose range that is subanesthetic?
* What is the evidence to support ketamine infusions as an adjunct to opioids?
* What are the contraindications to ketamine infusions in the acute pain setting and how might they differ from chronic pain scenarios?
* What is the evidence to support nonparenteral ketamine in acute pain?
* A review of evidence to support IV ketamine for patient-controlled analgesia.
The authors note that larger studies are still needed and hopefully will confirm the role of ketamine as an essential drug for pain management.
Conclusion
Given the safety profile of ketamine, including hemodynamic stability and lack of respiratory depression, combined with low cost and high availability and its expanding role in many aspects of pain management and depression, this agent should become a mainstay of many aspects of clinical practice. The importance of the glutamate system and the ever-evolving discoveries of how that system works combined with the interaction of ketamine within that system might suggest that we have not as yet uncovered the totality of the potential uses of the drug.
References