For more about Ketamine: Read Battle Tested: Ketamine Proves its Worth on the Front Lines
From club drug to horse tranquilizer to adverse events, ketamine has had a notorious (occasionally mythic) past. Today, ketamine is well established as a sedative, but it turns out “Special K” could play a bigger part in the emergency physician’s arsenal.
It is difficult to discuss clinical uses of ketamine without stirring up references to its use as an equine anesthetic or its notoriety as a drug of abuse. One participant in our low dose ketamine clinical trial left me a box of “Special K” as a parting gift. However, the worst of ketamine’s baggage as a therapeutic agent probably comes from its reputation for causing emergence phenomena in adults. Shortly after its FDA approval in 1970, ketamine was noted to occasionally cause severe hallucinations, agitation and delirium in adults; more recent literature has noted that this occurs in approximately 10 – 20% of adults receiving anesthetic doses of ketamine (≥ 1 mg/kg IV or ≥ 2 mg/kg IM) [1]. This is not to mention the tachycardia, hypertension, and emesis…
So why reignite interest in a drug that has a seemingly (and maybe unacceptably) high adverse event profile? While some of these events can be quelled by benzodiazepines, it also appears that many of these adverse events are dose dependent—by administering lower doses of ketamine, you can ameliorate the negative qualities of the drug while still retaining some of its beneficial effects. At higher doses (1 – 2 mg kg/ IV), ketamine is a dissociative anesthetic and a potent sedative. However, it also has analgesic properties (an advantage over an agent like Propofol which is a pure sedative) and these analgesic effects are still present even in lower doses. In addition, through its action as an NMDA receptor antagonist, ketamine can also potentiate the analgesic effect of opioids, allowing lower doses of opioids. These properties are the reason there is now a growing body of evidence supporting the analgesic potential of sub-anesthetic, or low dose ketamine for acute pain in the emergency department (ED).
Low dose ketamine has been well described as an adjunctive analgesic for peri-operative patients [2]. The problem with translating this literature into emergency medicine practice is that studies are very heterogeneous with regard to dosing, utilizing different amounts (0.15 – 1 mg/ kg), boluses versus infusions, and different rates of administration. Low dose ketamine given during general anesthesia would mask effects that may be unwanted in the awake patient. Lastly, a surgical model of acute pain may not generalize to the diverse nature of acute pain that is encountered in the ED.
In November 2014 we published the results of a small pilot RCT involving 60 patients testing one-time doses of 0.15 and 0.3 mg/kg IV as an adjunct to morphine (0.1 mg/kg IV) [3]. We found that over a 2-hour period, participants who received either dose of ketamine had superior pain relief compared to those who received morphine alone (considered standard care). By two hours however, for those who received 0.15 mg/kg of ketamine, the analgesic effect had dissipated, whereas for those who received 0.3 mg/kg analgesia was sustained.
Non-randomized ED trials and two pre-hospital studies reported either superior analgesia or opioid-sparing effects with adjunctive low dose ketamine [4-7]. The doses in these studies were either weight based (0.2 mg/kg) or a one-time dose ranging from 15 –35 mg.
The summary of these preliminary efforts seems to argue in favor of analgesic uses low dose ketamine. However, we cannot make practice recommendations without returning to the notion of ketamine and adverse events. Our study was underpowered to detect adverse events. However, a greater proportion of participants in the 0.3 mg/kg group experienced tachycardia, dizziness, and dysphoria. The tachycardia was self-limited, lasting less than 30 minutes, but nonetheless a potential concern in patients in whom a high heart rate would be undesirable. At this point, I believe (but cannot prove) that an RCT of greater size would show a higher degree of adverse events in the 0.3 mg/kg group. A large 530 person retrospective case series by Ahern et al. concluded that low dose ketamine was associated with an overall low number of adverse events (6%), none of which were deemed to be serious [8]. The majority of patients (92%) in this study received doses of 10 – 15 mg and doses over 20 mg IV were excluded—this corresponds to 0.25 mg/kg in an 80 kg individual. In addition, data was limited to what could be extracted from the medical record and transient events such as tachycardia or hypertension could have been missed. In examining the available evidence thus far, a starting dose of around 0.15 mg/kg or 10 – 15 mg seems to be reasonable for most adults.
The next logical question that follows is–who should receive low dose ketamine? Consider ketamine if the use of opioids is problematic–patients with opioid tolerance, opioid-induced hyperalgesia, true allergy—or if opioids are inadequate for pain control. A colleague recently shared an anecdote with me: a patient with renal colic had received ketorolac, 8 mg morphine and 4 mg of Dilaudid. Relief finally came after low dose ketamine, and the patient was able to be discharged home. Low dose ketamine is probably a good fit for poly-trauma or sickle cell patients, but these specific situations have yet to be tested.
Our hospital system is the process of approving clinical guidelines for the use of low dose ketamine. Guidelines will likely recommend low dose ketamine for moderate to severe pain (NRS ≥ 5) that is either refractory to opioids or where opioids are contraindicated, with caution for use in patients with unstable psychiatric disease, renal or liver dysfunction, or in whom tachycardia or hypertension would be undesirable.
There is a demonstrable need to have alternative and adjunctive analgesics at our disposal—and low dose ketamine is one additional tool that we can can add to our belts.
Photo by Karyn Christner.
REFERENCES
1. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. The American Journal of Emergency Medicine 2008;26:985-1028.
2. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane database of systematic reviews (Online) 2006:CD004603.
3. 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 EmergMed 2014 Nov; 21(11):1193
4. Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scandinavian journal of trauma, resuscitation and emergency medicine 2009;17:61.
5. Galinski M, Dolveck F, Combes X, et al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. The American Journal of Emergency Medicine 2007;25:385-90.
6. Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED: a retrospective case series. The American Journal of Emergency Medicine 2010;28:820-7.
7. Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. The American Journal of Emergency Medicine 2013;31:847-51.
8. Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. The American Journal of Emergency Medicine 2015;33:197-201.
9. Motov, S., et al., Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med, epub ahead of print, 2015.
4 Comments
I remember when I was a med student in the early 90’s. Ketamine was the “evil” drug associated with PCP and all its negative context. But now… This wonder agent has proven to be “the drug of choice” for pretty much anything. Come on…! Analgesic, anesthetic, induction agent, anti-epileptic, anti-depresant, chemical restrain, neuroprotective, and pediatric agent of choice. I am sure that if I try, it will help me re-grow my hair!
Pardon my ignorance, but I’m not familiar with the IN drug route. What does this mean?
IN is intranasal route. A syringe is filled with the drug of choice and a small foam applicator is attached which helps aerosolize the drug.
I routinely use low-dose ketamine in hospice for pain control. It works VERY well, especially when given in addition to opioids/those with opioid-induced hyperalgesia. I give 10-60mg po up to QID (I believe this is just the IV formulation given orally) or 25-100mg/24 hours continuous SC or IV infusion (no bolus). Pts will get hypersalivation and tachy/hypertensive, but both are moderate. Pts on it for longer can develop vivid dreams and hallucinations. They do not become sedated or confused. Many can have a major reduction in opioid dose after starting this.