Motov’s Cocktails: Sub-Dissociative Ketamine

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In this ongoing conversation with Dr. Sergey Motov, a vocal proponent of non-opioid analgesia, we discuss how ketamine can be a smart alternative to opioids if you know how to dose it. Interview by Nicholas Genes, MD, PhD.


Sergey Motov has published a lot in recent years on the ED uses of ketamine, specifically two trials and an editorial on Sub-Dissociative Ketamine (SDK) dosing in the ED. I had the chance to talk with him about his research and ED practice – how and when he uses SDK in the ED.

EPM: I’m seeing a lot of research, from you and others, saying that ketamine, as an analgesic (0.3mg/kg), is comparable to morphine (0.1 mg/kg). Both drugs both show comparable drops in pain scores, at 30 minutes, 90 minutes, 120 minutes. And you have a randomized trial from 2015 actually showing a bigger drop in pain with ketamine, at 15 minutes – complete resolution of pain in a substantial fraction of patients! It’s remarkable and I can see the appeal. Though, from your data, I wonder if there’s something of a rebound effect. Do some patients feel the pain coming back, at 30 or 60 minutes?

Sergey Motov: The papers you are referring to demonstrated effective analgesic effects of IV SDK up to 30 min post-administration with subsequent need of either ketamine re-dosing or a rescue opioid. The reason behind such a short-lived analgesia is explained by ketamine’s onset of action and half-life: kicks-in in 1 to 5 min, half-life of 15-30 min. Therefore, right after the initial loading dose, I always initiate a continuous SDK infusion at 0.15 mg/kg/hr with titration every 30 min until pain is optimized or psychoperceptual adverse effects become very bothersome to patients.

EPM: I’m glad you’re tackling the side effects of ketamine in your latest trial. Many supporters of ketamine tend to focus on its favorable effects on pain compared to morphine. That’s fine, but once you’ve seen a patient get a lower dose of ketamine yet still have a “bad trip” it makes you nervous to use it again. I know it’s a short-lived effect, but it’s the biggest obstacle, for me (while the patient is freaking out, the nurse is alarmed and everyone is stuck at the bedside. Minutes seem like hours). By the book, we should be giving SDK as an IVP over 3-5 min, but in many EDs I bet it goes in faster – and patients quickly feel a sense of unreality. Would you agree?

Motov: Absolutely. When it comes to IV SDK analgesia, the rates and onset of side effects are directly related to a time/rate of administration. Ketamine is very lipophilic and rapidly crosses blood-brain barrier. Intravenous push (1-3 min) of ketamine even in sub-dissociative doses will lead to nearly instant saturation/blockade of NMDA receptor sites with resultant development of psychoperceptual effects (“bad tripping”). And as you mentioned, despite its short duration, it can be frightening for patients, their families and health care providers. That is why it has been our practice in the ED to administer SDK at 0.3 mg/kg over a 15 min time frame.

EPM: So in your new trial in AJEM, you did a clever blinding – patients got both an IVP and a slow infusion – you just randomized as to which patients got saline vs ketamine. And sure enough, the feeling of unreality was higher in the IVP group compared to the slow infusion. But I must say, this feeling of unreality that was reported – almost all the IVP patients had it (~92%), and over half the slow infusion patients had it (54%). Is this higher than you expected? It seems higher than other trials. Is it because you were specifically looking for it?

Motov: The rates of feeling of unreality in IVP group were indeed higher than I expected. And much higher than the reported rates of 52-78% in other trials. However, based on my personal experience, all patients that I have ever administered intravenous push-dose SDK developed that feeling of unreality (“floating”, “quick sanding”) of different severity. Your assertion is correct as we did look specifically for side effects that are unique to dissociative anesthetics by utilizing SERSDA (side effects rating scale of dissociative anesthetics). By doing so we were able to capture more, if not all, patients with feeling of unreality in comparison to other trials.

EPM: You note that slow infusions via pump need not be a barrier to care – they can be pre-programmed for ketamine, and all the nurse has to do is enter the patient’s weight. But come on, there’s no question that an IV push of morphine is going to be easier to administer than a slow infusion of ketamine. Can we consider just hanging a bag of dilute ketamine and letting it drip in over 30 minutes or so?

Motov: The slow infusion of SDK at 0.1-0.3 mg/kg in 100 ml of normal saline can be administered in the ED without a pump over 15 min period. As an example, in our ED we do not routinely use an IV infusion pump for a short infusion of SDK as our nurses after six years of doing so are very comfortable with no pump approach by adjusting the flow rate to a 15 minutes’ time frame.

EPM: Here’s a related question: in your EMR commentary you state that, even though SDK ketamine is safe, agencies still (erroneously) recommend monitoring rhythm and pulse ox. In your last AJEM paper though, you say (outside of research) these ketamine SDK patients don’t need monitoring. What can our readers do, at their EDs? If they want to use SDK ketamine, should they check with their director or their pain committee before trying SDK without a monitor? Or should they just override the nurse’s concerns?

Motov: The data from EM literature that support the utilization of SDK in the ED for management of variety of acute and chronic painful conditions clearly demonstrate safety of this agent and lack of any measurable effect on blood pressure and oxygen saturation. The only limiting factor to SDK use is the severity and intolerance of pyschoperceptual side effects. The problem is, however, that many agencies look at ketamine as a sedative with dissociative properties regardless of the dosing used and require full procedural sedation protocol with monitors, pulse oximetry and even consent. I would strongly encourage our readers to talk to their administration, their pain committee and even anesthesiologists to create at least departmental policy on SDK administration without a need for monitoring. More importantly, ED nurses must be on-board with the protocol that will allow SDK to be given without a monitor. After all, nurses are the ones who will be administering ketamine and their opinions and participation in protocol creation are invaluable to its successful implementation in the ED. I would definitely not advise to override nurses’ concerns.

EPM: Fair enough. Ok, I think I can speak for most emergency physicians when I say we’re comfortable with ketamine as a dissociative agent at higher doses, and we know now it’s analgesic properties, particularly at lower doses… but you recently called it anti-tolerance, anti-allodynic, and anti-hyperalgesic. This is opening up whole new pathways for me. Can you explain?

Motov: As you pointed out, ketamine is a dissociative agent that traditionally has been called a “triple A” drug by providing anesthesia, amnesia and analgesia. With the discovery of NMDA/glutamate receptor complex, and a better understanding of its role in transmitting pain signals, ketamine has gained enormous popularity in the world of analgesia. Ultimately, after tissue injury, the NMDA/glutamate receptor complex is activated in the dorsal horn of the spinal cord. These receptors are pivotal in developing hyperalgesia, allodynia and ultimately, central sensitization and wind up phenomenon, which leads to the development of persistent and neuropathic pain as well as opioid-tolerant pain.

Ketamine in sub-dissociative (low, analgesic) doses non-competitively blocks the NMDA receptors and becomes a different kind of “triple A” agent, with its antihyperalgesic, antiallodynic and antitolerance effects. This mechanism of action of ketamine is responsible for its utility in managing a variety of acute and chronic (neuropathic, malignant, opioid-tolerant, opioid-induced hyperalgesic states) painful conditions as adjuvant analgesic, or even as a single agent.

EPM: I’m surprised ketamine has such a role disrupting the wind-up phenomenon. I confess, I understood the wind-up phenomenon in the context of lidocaine or bupivacaine. It made sense to me that, as pain signal mediators built up at the site of injury, or in the spinal cord, locally-injected lidocaine would disrupt this process at the source. Opioids and central-acting meds do not – they just kind of mask the local pain messages. And so when opioid drugs wear off, all these local and spinal inflammatory mediators are still present, still active, and continuing to signal pain. That’s why ED patients who get even short-acting lidocaine tend to need less pain medication, hours and days later. I’m surprised this is true of ketamine as well – but was my mental image of wind-up too simplistic?

Motov: It is a fairly accurate mental image of the wind-up phenomenon. Wind-up is a frequency-dependent excitability of neurons in the dorsal horn of the spinal cord after an intense and/or persistent repetition of afferent nociceptive stimuli. The voltage-gated sodium channels that are effectively blocked by local anesthetics modulate this nociceptive excitability but the activation of the NMDA/glutamate receptor complex is a necessary step in development of wind-up phenomenon. And that is how ketamine’s anti-NMDA blocking property disrupts wind-up.

EPM: Ok – so even if patients report the same pain relief with ketamine as they would with morphine, the ketamine’s better for them, because it’s disrupting wind-up. Odds are, patients who get ketamine after an acute injury are going to need fewer pain meds down the road, because those pain mediators never build up to the same level.

Motov: You are correct. The disruption of wind-up by ketamine may result in significantly lesser requests for additional and /or rescue analgesia by patients in the ED especially in the setting of acute injury. However, in chronic/persistent pain states, the wind-up phenomenon is severe enough that it might not respond to a single dose of SDK. That is why in properly selected patients, a continuous infusion of low-dose ketamine will inhibit that central hyperexcitability and provide strong hypoalgesic effects.

EPM: I can’t let this opportunity pass me by: How should I prepare intranasal (atomized) ketamine, and when should I use it? Is it for kids, or adults with difficult access? Should I be nervous that the dose is 1 mg/kg? That’s a higher dose than SDK IV, and going directly into the CSF! In a way, I think IN ketamine requires as much of a culture change as setting up an IV pump and convincing nursing it’s OK not to monitor. So I want to pick my battles, choose the right patients, and do it right.

Motov: You are absolutely correct about the fact that ED ketamine utilization for analgesia requires a major culture change regardless of which route of administration is being used. Having said that, intranasal route is extremely useful for both pediatric and adult patients with traumatic and non-traumatic acute pain as an initial analgesic approach (until IV access is established). The higher IN dose is based on the fact that systemic bioavailability of intranasal ketamine is 20-50% of the IV route. However, that 1mg/kg dosing is associated with high rates of adverse events, mainly dizziness, drowsiness and dysphoria. The lesser dosing of 0.5-0.75 mg/kg was found to be significantly inferior with respect to analgesic efficacy to 1mg/kg dosing regimen.

Another important issue of IN ketamine administration revolves around a need for highly concentrated solutions, especially for adult patients: 100mg/ml for adults and 50mg/ml for children as the optimum dosing per nostril is 0.3-0.5 ml. But on the bright side, intranasal route allows titration of ketamine, which might lead to better analgesia and lesser degree of adverse events, by using smaller than 1 mg/kg dosing regimens.


REFERENCES

  1. Vadivelu N, Schermer E, Kodumudi V, Belani K, et al. Role of ketamine for analgesia in adults and children. Role of ketamine for analgesia in adults and children. J Anaesthesiol Clin Pharmacol. 2016 Jul-Sep;32(3):298-306. doi: 10.4103/0970-9185.168149.
  2. Walker SM. Mechanisms of inflammatory hyperalgesia. In: Macintyre PE, editor. Clinical pain management (acute pain). 2nd edition. London: Hodder & Stoughton Limited; 2008. p. 20-28.
  3. Herrero JF, Laird JM, López-García JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol. 2000 Jun;61(2):169-203.
ABOUT THE AUTHORS

Dr. Motov is an Attending Physician and Associate Research Director in the Department of Emergency Medicine at Maimonides Medical Center with particular interest in safe and effective analgesia in the ED.

SENIOR EDITOR A specialist in emergency medicine informatics at Mount Sinai in Manhattan, Dr. Genes is EPM's resident tech guru. He practices emergency medicine at Mount Sinai Hospital but can be found sharing his wit and wisdom all over the web.

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