Synthesized at Wayne State in 1962, ketamine is a non-competitive NMDA antagonist used most often for moderate sedation and as part of rapid sequence induction (RSI). When used at such doses – generally greater than 1mg/kg IV – ketamine has amnestic, sedative, and profound analgesic properties. Ketamine is used extensively on the battlefield by US forces for analgesia in combat-ineffective troops requiring medical evacuation.1 One review of combat analgesia characterized ketamine as “an almost ideal analgesic because of its profound pain relief, its potentiation of opioids, its role in preventing opioid hyperalgesia, and its large margin of safety.”2
This discussion and review will be limited to IV, low dose ketamine (LDK) given for analgesia – although it can also be given IM and IN (especially helpful in the prehospital, pediatric, or agitated patient setting). LDK has been evaluated for all variants (MSK, abdominal, trauma) of acute and chronic pain encountered in the ED. Ketamine affects several other neurotransmitters (including opioid mu receptors) in addition to NMDA receptors, which remain largely unaffected at LDK doses. This may explain why dissociation does not occur at LDK doses, while analgesia and opiate potentiation remain.
LDK is sometimes termed “sub-dissociative dose” ketamine (SDDK). This is somewhat improper; all LDK falls within the sub-dissociative dose range, but not all sub-dissociative ketamine is LDK. As an example, 0.7mg/kg of ketamine may not dissociate your patient, but it will do far more than provide anesthesia.3 At present, many hospitals limit the use of ketamine to procedural sedation, as most systems classify it as a general anesthetic.
What is the evidence for efficacy of analgesia?
LDK has been very successfully shown to decrease pain scores, both in conjunction with morphine4,5,6,7 and as a standalone treatment.3,8,9,10 It appears to be non-inferior to morphine when used alone at doses of 0.15 or 0.3mg/kg. Onset usually occurs in 1-3 minutes and effects are observed for approximately an hour and a half, with peaks observed in the earlier portion of that time period.8,9 Ketamine has been shown to potentiate the effects of morphine, and has been uniformly shown to reduce required doses of morphine when administered together.5 Two studies that asked patients whether they would like to receive LDK for similar pain in the future found 67% and 85% patients answering in the affirmative.7,10
One recent literature review of four randomized-controlled trials of LDK did discuss two trials with somewhat equivocal results. The first of these showed LDK to be non-inferior to fentanyl.11 The second found that patients pre-medicated with 0.1mg/kg of morphine who then received 0.2mg/kg ketamine required significantly fewer rescue doses of 3mg morphine (1.0 vs. 2.3), but showed no change in their VSAS scores – a finding that is difficult to explain.12
Bottom Line: LDK plus morphine provides better pain relief than morphine alone and reduces opiate consumption. Because high-quality evidence for this indication is more numerous, most new ED LDK policies may limit LDK to opiate-refractory pain or combination therapy. However, LDK alone certainly provides efficacious analgesia, certainly potentiates and decreases subsequent opiate requirements, and is likely non-inferior to morphine when used alone.
A truly large-scale, DB-RCT is needed to more convincingly elucidate whether LDK analgesia is superior to morphine when used alone. Miller (2015) and Beaudoin (2014) provide good templates for a larger-scale trial.
Which doses are best supported by evidence?
LDK doses range from 0.1-0.4mg/kg. Anecdotally, many physicians support a starting dose of roughly 0.1-0.2mg/kg. Side effects appear to be dose-dependent.5 Ketamine should be pushed slowly over at least one minute, which some authors feel reduces the likelihood of immediate side effects such as disorientation.
Most controlled studies dose ketamine at 0.15 or 0.3mg/kg, as these are the well-studied doses in post-op anesthesia literature.5 Ahern (2015) followed initial doses with a 20mg/hr infusion with good results, increasing analgesia duration to 120 minutes with pain scores that appear superior to push-dose only LDK, although with no control group.7
‘Recreational’ dosing traditionally starts around 0.4mg/kg, so dosing higher than that runs the risk of placing your patient in the recreational “K-hole”.
Bottom line: Dosing of LDK has been effectively studied from 0.1-0.3mg/kg, with some studies using a uniform 10mg or 15mg dose.
A large-scale, DB-RCT is still needed to effectively determine an optimal dose, whether weight-based dosing is required, and what rate should be used. LDK infusions have a theoretical advantage, but require more research.
What side effects/ADE will not occur?
Anticipation of emergence reactions is the number one reason why physicians fear use of LDK in the ED.10 However, emergence reactions are nearly impossible with properly dosed LDK, and none were reported in any study.3,4,5,6,7,8,9,10,13 Ketamine does not increase ICP.14 It does not inhibit respiratory drive to the point of apnea at any dose.14,15,16 Up to 100-fold (50mg/kg) overdoses have been reported with no adverse events other than prolonged, otherwise typical sedation.8,16
What side effects/ADE will occur?
By far, the two most common side effects are dizziness and mild dysphorias, sometimes referred to as ‘psychomimetic reactions’ and including ‘disorientation’ or ‘negative feelings’. Mild dysphoric events are far shorter and less severe than true emergence reactions.13 The incidence of these ranges from 3-15%, depending on the study’s definition and reporting, as well as dose.5,8,9,13 They typically occur immediately after administration and quickly resolve. They appear to be dose-dependent, but that dose may differ per patient.5 An approach where you literally prepare and coach the patient through the experience prior to giving the medication has, anecdotally, been shown to reduce the incidence of the patient experiencing an emergence or psychomimetic reaction.10,13
Dizziness is, by far, the most common ADE, reported in roughly 20% of patients in RCTs polling patients on side effects.8,9 Another study showed dizziness in 45% and 53% of patients immediately after receiving .3mg/kg; of note, 31% of patients receiving morphine had the same complaint.5,9
In one large (n=530), retrospective chart review, the following notable findings were shown; 6% of patients experienced an adverse event documented in the chart. 7 patients (1.5%) developed transient hypoxia – 4 of those also received hydromorphone and all but 1 (COPD requiring BiPAP) resolved with 2L NC. 18 patients (3.5%) developed “psychomimetic/dysphoric disturbances” which included dizziness or bad dreams; only 3 of those received benzos and disposition was unaltered in all of them. 5 patients (1%) experienced emesis, with no cases of documented or concern for aspiration.13 While this study was limited by its retrospective design and lack of dosing protocol, its strength is that, presumably, only clinically apparent ADEs were documented. This, in addition to the fact that lower doses tended to be used, likely account for the decrease in ADEs. Most importantly, any incidents of true emergence phenomenon, laryngospasm, apnea, or cardiac arrest would certainly have been detected if they occurred. None did.13
Multiple studies comparing ketamine to morphine find adverse event rates to be similar; these events are dizziness and dysphoria in ketamine, nausea and respiratory depression in morphine, thereby highlighting the superior safety profile of ketamine as compared to morphine.
Bottom line: LDK is most certainly safe, and all of the common side effects appear to be benign. There were no incidences of emergence reaction, laryngospasm, apnea, cardiac arrest, or anything requiring alteration of disposition documented in any study. Dizziness and mild dysphorias – also termed disorientation, feelings of unreality, negative feelings, or psychomimetic reactions in various studies – are the most common side effects. When compared head-to-head with morphine, adverse event rates tend to be similar. Obviously, side effects for opiates are neither uniformly benign nor uncommon.
When is LDK indicated?
LDK should be considered any time your patient is in pain. It should be considered for patients who do not want to receive narcotics (i.e., previous addicts), patients who are hypotensive or have a tenuous respiratory status, patients with difficult-to-control pain (i.e., chronic opiate-tolerant, sickle cell, oncologic), or patients in whom opiates would worsen their condition (i.e., constipation).3,8 Furthermore, there is some evidence that ketamine prevents the “wind up” phenomenon seen in chronic pain, and may have long-lasting analgesic effects in patients with chronic pain.10
Additionally, LDK can be used in concert with opiates in patients who might require more opiates – either due to tolerance or injury – than could be safely administered without concern for respiratory depression in poorly monitored areas of the ED.1
I hope this provides some good evidence to you for the practice of using low dose ketamine for analgesia.
Reid K Smith, M.D.
Sinai-Grace Emergency Medicine
- Dickey N, Jenkins D, Butler FK. Prehospital use of Ketamine in Battlefield Anesthesia 2012-2013. 2012. Available at http://www.specialoperationsmedicine.org/documents/TCCC/06%20TCCC%20Reference%20Documents/DHB%20Memo%20120308%20Ketamine.pdf
- Black IH, McManus J. Pain Management in current combat operations. Prehosp Emerg Care 2009; 13(2):223-7. PMID:19291561
- Beik N, Sylvester K, Rocchio M, and Stone MB. Evaluation of the Use of Ketamine for Acute Pain in the Emergency Department at a Tertiary Academic Medical Center. Pharmacology & Pharmacy 2016; 7:19-24. http://dx.doi.org/10.4236/pp.2016.71003
– Retrospective chart review, n=25. Many patients received opiates as well. Poor, retrospective methods, however no significant ADE.
- Jennings PA, et. al. Morphine and Ketamine Is Superior to Morphine Alone for Out-of-Hospital Trauma Analgesia: A Randomized Controlled Trial. Ann Emerg Med 2012; 59(6):497-503. PMID:22243959.
– Pre-hospital, open label RCT, n=135, MS 5mg followed by initial 10-20mg LDK and 10mg LDK q3m until resolution (mean 40.6mg), vs. 1-5mg MS q5m. MS + LDK was superior.
– “Emergence phenomenon was reported by paramedics in 4 of the ketamine group… which included symptoms such as dysphoria, agitation, and hallucinations.” These sound like mild, dysphoric events. Given the overwhelming evidence in other trials where no such reactions were found, and the fact that these are not described as true emergence reactions and required no medications, I’ve not characterized them as such. It should also be noted that the mean amount of ketamine administered in this trial was likely higher than the total administered to any single patient in any other study reviewed here.
- Beaudoin FL, et. al. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med 2014; 21(11):1193-1202. PMID:25377395
– DB-RCT, n=60, 0.1mg/kg MS vs. MS + 0.15mg/kg LDK vs. MS + 0.3mg/kg LDK.
– Reviewed at recent SGH journal club. LDK + MS superior to MS alone for pain reduction. No emergence reactions.
- Lester L, et. al. Low-dose ketamine for analgesia in the ED: a retrospective case series. Am J Emerg Med 2010; 28(7):820-7. PMID:20837262
– Retrospective chart review, n=35, early (2004-2006) case study in which LDK was primarily used for abscess drainage in opiate-tolerant patients in conjunction with opiates. No significant adverse events.
- Ahern TL, et. al. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med 2015; 16(7):1402-9. PMID:25643741
– Descriptive observational, n=40. LDK IVP of 15mg, followed by 20mg/hr infusion. 436 of 456 observed sedation scores were minimal sedation, 20 were mild sedation. No deep sedation. No ADE beyond dizziness, ‘feelings of unreality’. 85% of patients were satisfied.
- Miller JP, et. al. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med 2015; 33(3):402-8. PMID:25624076.
– DB-RCT, n=45, MS 0.1mg/kg vs. LDK 0.3mg/kg
– Found nearly no difference between 2 groups, with onset of relief faster with LDK. ADEs were equal by incidence, none severe.
- Motov S, et. al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med 2015; 66(3):222-9. PMID:25817884
– DB-RCT, n=90, 0.1mg/kg MS OR 0.3mg/kg LDK. No serious ADEs. There were essentially no differences between groups.
- Richards JR, Rockford RE. Low-dose ketamine analgesia: patient and physician experience in the ED. Am J Emerg Med 2013; 31(2):390-4. PMID:23041484
– Descriptive observational, n=24, study of patients receiving LDK, pain reduced from 8.9 to 3.9 and 67% of patients would receive it again. No emergence reactions.
- Sin B, Ternas T, Motov SM. The Use of Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med 2015; 22(3):251-7. PMID:25716117
– Review of 4 LDK RCTs. The trials were very heterogeneous with entirely different methods and outcomes; this was not a meta-analysis. In their discussion, the authors admit that “the review suggests… limited evidence to either support or refute” LDK, however they acknowledge that the reviewed studies had “small sample sizes” and “various methodologic flaws” including unclear documentation and missing data.
- Galinski M, et. al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med 2007; 25(4):385-90. PMID:17499654
– DB-RCT, n=65. All patients given 0.1mg/kg MS, followed by 0.2mg/kg LDK or placebo. The mean number of 3mg MS rescue doses was significantly decreased (1.0 vs. 2.3) in the LDK group, however, the average VSAS between the two groups showed no difference. Poor ADE reporting.
- Ahern TL, et. al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med 2014; 33(2):197-201. PMID:25488336
– Retrospective chart review, n=530, of patients receiving LDK under LDK protocol. “Most” patients received 10-15mg LDK.
- Cohen L, et. al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Am J Emerg Med 2015; 65(1)43-51. PMID:25064742.
- Tobias JD, Leder M. Procedural Sedation: A review of sedative agents, monitoring, and management of complications. Saudi J Anaesth 2011; 5(4):395-410. PMC3227310
– This is an excellent review of procedural sedation agents.
- Green SM, et. al. Inadvertent ketamine overdose in children: clinical manifestations and outcome. Ann Emerg Med 1999; 34(4):492-7. PMID:10499950
– Solicited case reports of 9 cases where peds received 5-, 10-, or 100-fold overdoses of Ketamine. 100-fold OD was a 16kg child who received 800mg of Ketamine. He was prophylactically intubated but at no point showed signs of respiratory depression and his sats remained at 100%. Sedation lasted 9 hours and he was discharged 17 hours after administration.
As a reminder, you can easily access almost any article from any computer by navigating to https://library.wayne.edu/resources/journals/, logging in with your WSU access ID (usually two letters followed by 4 numbers), and searching for the article by PubMed ID (PMID).