“B-Sides” in Analgesia

by Meghan Spyres

Ketamine was gifted to the world as a result of investigations into its evil older brother: phencyclidine (PCP). PCP, commonly known as ‘angel dust’ (quite the misnomer, Urban Dictionary suggests the use of the more fitting ‘devil dust’. . .) was initially used as a pharmaceutical in the 1950s under trade name Sernyl™. A high prevalence of suboptimal side effects, including psychosis and catatonia, led to its quick withdrawal from clinical use. Attempts to find a more user-friendly option gave us ketamine, with brand-names including Ketaject, Ketalar, or Ketavet for our 4-legged friends. Ketamine has been clinically available as an anesthetic in the US since 1970, and, unsurprisingly, abuse was reported as early as 1971. Physicians joined the recreational ketamine party in the 1980s, and it was marked as a Schedule III drug in 1999 under the Controlled Substance Act, although this did not appear to impact its recreational use. Facilitated by internet availability, ketamine (and its derivatives including methoxyketamine) continue to be abused, however, its popularity never soared and use has remained low since the early 2000s.^​1​

While popularity as a drug of abuse remains stagnant, medical use of ketamine is experiencing a resurgence from its relegation to the D-list of medicine. It is now a go-to agent for procedural sedation and severe agitated delirium. It is increasingly used as an adjunct in alcohol withdrawal and is even being studied as a treatment for depression.^​2​ Its analgesic properties have been understood for decades, but misunderstanding and overblown fear over psychiatric side effects likely limited its widespread use. Now deep into the era of the opioid epidemic, ketamine’s appeal as an analgesic for pain is more apparent and harder to ignore.

To understand how ketamine functions as an analgesic we must first understand the N-methyl-D-aspartate (NMDA) receptor.

Like PCP, ketamine’s clinical effects are largely due to its antagonism at the NMDA receptor. The NMDA receptor is one of 3 main ionotropic glutamate receptors (as opposed to the metabotropic G-protein coupled glutamate receptors) along with AMPA and kainate. The NMDA receptor is a voltage and ligand-gated channel that results in Ca2+ and Na+ influx when activated. For the receptor to be activated two separate processes must occur. Glutamate and glycine must bind to their respective sites on the receptor (ligand-gated), and depolarization must occur (voltage-gated) to displace Mg2+ which at rest obstructs the channel.

In a gross oversimplification, these receptors mediate glutamatergic (excitatory) neurotransmission in the CNS and play a role in memory, learning, and synaptic plasticity. Ketamine acts as a non-competitive antagonist of the NMDA receptor by binding to the PCP binding site in the internal portion of the channel, thus preventing glutamate-mediated neurotransmission of cations. This functions to dampen neuroexcitation with resulting anesthesia, analgesia, and psychoperceptual clinical effects.^​1,3​

How exactly does this translate into pain relief? NMDA antagonism results in reduced cerebral activation (primarily in the somatosensory cortex, insula, and anterior cingulate cortex) in response to painful stimuli.^​4​ So there is a disconnect (dissociation) between the pain stimulus and your brain’s ability to recognize it. Additionally, at the level of the spinal cord, afferent spinoreticular pathways are blocked and descending inhibitory serotonergic pathways are enhanced (at least in rats) furthering analgesic effects.^​5​ Ketamine has also been shown to bind opioid receptors. Its low affinity for these receptors, however, suggests this not to be a mechanism of analgesia at recreational or anesthetic doses.^​6​ This is supported by the failure of naloxone to reverse ketamine-induced analgesia.^​7​ Lastly, there is evidence that nitric oxide synthase inhibition contributes to ketamine’s analgesic effect.^​8​

Interestingly, via interactions with opioid receptors in the CNS, the NMDA receptor plays a role in the development of opioid tolerance and opioid hyperalgesia.^​26​ Antagonizing this receptor with ketamine blunts this effect at its origin, thus acting to prevent the phenomenon. Read here for receptor-level detail on how this really works, and for an overall great paper on ketamine pharmacology.^​27​ So by using ketamine for pain, not only are we avoiding overusing or introducing someone to opioids, but we may also be helping to prevent some of the receptor level negative consequences of chronic opioid use.

There is solid evidence (RCTs) supporting both the use of ketamine as an adjunct to opioids and as a single agent for pain relief. When used as an adjunct, improved pain scores are reported and some find lower total doses of opioids are needed.^​9–11​ When compared to morphine as a single agent, ketamine achieves equal or improved pain scores.^{​12–14​} Ketamine may also reduce pain faster^​14​ but have a shorter duration of action, depending on how it is delivered and the dose (more on this below). For chronic pain, the evidence appears to be a bit more muddled, likely due to the diverse etiology of chronic pain and the variety of doses and routes of low-dose ketamine used in trials.^​15,16​ This post focuses on ketamine for acute pain in the ED.

When considering ketamine as an analgesic, the big questions for most clinicians are how do we use it (i.e., dosing), when do we use it (i.e., which patients), and is my patient going to totally freak out?

First, let’s tackle the dosing

When ketamine is used for analgesia it is often referred to as “subdissociative ketamine” (SDK). I prefer the term “low dose ketamine” (LDK) because there exists a whole range of wonderful and terrifying effects between the very low dose we want for analgesia and full dissociative dosing we use for agitated delirium. Most notably, both the recreational dose (the dose that gets you high) and partially dissociated dose (the infamous “K-hole” dose patients and clinicians alike want to avoid) are technically SDK dosing. We do not want either of these when using ketamine for analgesia. So LDK for pain, how do we do it?

Doses of 0.15-0.3 mg/kg IV are considered LDK for analgesic purposes, which translates to 10-20 mg IV for our standard 70 kg male. Most favor using the higher dose range of LDK as it is anecdotally reported as more effective, including Ruben Strayer, the person who first introduced me to ketamine for analgesia as a resident. It may last longer, however, studies directly comparing the two are limited.^​9​ When used as an adjunct to morphine, both doses appear to have similar efficacy.^​9​ The primary concern when using 0.3 mg/kg is the increased risk of side effects, particularly if you slip into the recreational dosing zone. These effects are typically well tolerated as long as you stay under the partially dissociated dose range (approximately 0.5-1 mg/kg).

Pushing ketamine rapidly will also increase its psychiatric effects^​17​ although bolus dosing of LDK is effectively used. Some authors recommend using a bolus followed by a drip, and others recommend a brief infusion. The latter has been shown to effectively reduce psychiatric side effects by nearly 40% when using infusions of 0.3 mg/kg over 15 minutes and is a reasonable approach.^​17​ Institutional guidelines may limit your ability to use ketamine drips and this may be a nice alternative.

In which patients should we be using LDK as an analgesic?

Opioids remain our first-line agents for severe acute pain in the ED. But as the opioid epidemic rages on, we are compelled to consider alternatives. Additionally, there are certain populations in which opioids are not the best choice. These cases generally fall under two categories.

Opioids are not effective

For people on opioid antagonist therapy (OAT) such as naltrexone for EtOH dependence or buprenorphine for opioid use disorder (OUD), mu receptors are less available and therefore opioids cannot easily provide effective analgesia. Additionally, for people chronically on opioids for any reason, you will be hard-pressed to achieve effective analgesia at doses you are comfortable giving. What’s more, some patients will simply have severe refractory pain despite high doses of opioids. LDK is a great option for these patients.

Opioids are not desirable

There are several scenarios in which opioids may be high risk for your patient.

A patient in recovery who suffers a femur fracture, for example, requires significant pain control. These patients are likely to be harmed by re-exposure to opioids but this should not prevent them from receiving adequate analgesia.

The elderly represent a high-risk group for opioids, both in terms of toxicity and underdosing. Altered absorption, metabolism, and elimination of drugs, along with the high prevalence of polypharmacy in older adults put them at risk for opioid toxicity.^​18​ What’s more, is that studies show clinicians often undertreat pain in the elderly, likely due to this fear.^​19,20​

Other groups in which opioids are suboptimal include patients with impaired renal function (morphine metabolites build-up) and those with underlying lung disease (increased morbidity from opioid-induced respiratory depression)

Lastly, in a hypotensive critically ill patient with pain such as a polytrauma after an MVC, the depressive hemodynamic effects of opioids make ketamine, and its associated sympathomimetic side effects, a better option for analgesia.

In which patients would LDK be harmful?

Although LDK might seem like the answer to all your prayers, no drug comes without consequences. In addition to NMDA antagonism, ketamine inhibits the reuptake of catecholamines causing a sympathomimetic clinical effect. This is often a welcome side effect in the critically ill, but may be of concern in cases of aortic dissection or other conditions in which increasing heart rate or blood pressure would be detrimental. (Needless to say, increased intracranial pressure is NOT a contraindication to ketamine^​21​)

LDK’s primary concerning adverse effects include nausea and psychoperceptual effects including hallucinations/feelings of unreality, dysphoria, and dizziness.^​22​ When properly dosed (0.3 mg/kg IV maximum), partial dissociation (K-hole) should not occur, however, it is a good idea to warn patients about the possible psychoperceptual effects before using LDK. Despite these reactions, patient satisfaction scores often favor ketamine.^​22​ What about using LDK for patients with schizophrenia? Not surprisingly, the available evidence suggests that LDK transiently increases schizophrenic-like symptoms (ketamine’s psychoperceptual effects) in these patients, as it does in healthy volunteers.^​23,24​ Lasting consequences are not seen. Read here for a good FOAM lit review on the topic. For my practice, I would likely steer clear of ketamine for schizophrenic patients depending on the risk/benefit breakdown for alternatives, but it is certainly not a hard contraindication.

Respiratory depression can and does occur with ketamine, however, it is dose-related and should not occur at the low doses used for analgesia.^​25​ LDK was recently studied for analgesia in the elderly and 2 patients (6.7%) had brief hypoxic episodes requiring oxygen.^​22​ Apart from this, there were no serious side effects including other intervenable vital sign abnormalities or respiratory distress. I like to have patients on a pulse ox when they receive IV morphine, and I would do the same for ketamine, but this is distinctly not procedural sedation and does not require associated intensive monitoring.

Despite historic perceptions and pop culture associations, in Medicine, ketamine is neither our angel dust nor our devil dust. LDK, in particular, is associated with a very low side effect profile and may be an excellent, and likely underutilized, opioid alternative or adjunct for pain in the Emergency Department. Though ketamine may not be the ideal agent for every patient (fortunately nothing is, which may serve to keep us employed as algorithms take over medicine), it absolutely has its role. Consider using LDK for your next patient with severe pain refractory to opioids, in your hypotensive trauma patient, or in your patient on OAT with acute pain who prefers not to risk re-exposure to opioids. Looking for a little more support to back you up? ACEP even has a policy advocating for LDK in the ED, along with a great policy resource and education paper.