Director of Orthopedic Anesthesia
Sidney Kimmel Medical College
Thomas Jefferson University
Virtually anyone in health care who treats patients has witnessed the devastating effects that the current opioid epidemic has had on our communities. Patients who present with substance use disorder challenge even the most experienced clinicians. Pain management is extremely difficult and alternatives to opioids are highly desirable.Ketamine, a phencyclidine derivative that has been in clinical use as an anesthetic agent since 1964,1 possesses many of the qualities that an ideal opioid alternative would have: potent analgesia,1-3 minimal intrinsic respiratory depression,4,5 a mostly favorable hemodynamic profile,4,5 and manageable adverse effects.3,6-8 Although only approved as an anesthetic agent,9ketamine when used in low or subanesthetic doses provides effective analgesia for a variety of painful conditions, as well as serves as a powerful adjunct during the perioperative period.
Published in June 2018, the acute pain guidelines developed and answered a series of 6 questions to help guide practical management of subanesthetic ketamine for acute pain. Although definitive answers were not possible in several cases, given weak or lack of evidence, the best available evidence was analyzed, which in some cases involved expert opinion.
Question 2 dealt with dosing and what the term subanesthetic refers to. The committee recommended that bolus doses should not exceed 0.35 mg/kg and infusions not exceed 1 mg/kg per hour.2 However, adverse effects can certainly occur at lower doses, which the guidelines acknowledged. In my practice, where ketamine is used frequently for opioid-tolerant patients perioperatively, as well as for patients with exacerbations of chronic painful conditions, we do not routinely exceed 1 mg/kg per hour with our infusions.
There are certainly scenarios in which we will permit higher rates, such as patients admitted primarily for ketamine therapy for complex regional pain syndrome exacerbations or refractory headache. In these patients, whose admission is largely focused on ketamine, other options usually have been exhausted, so they may be more willing to tolerate mild hallucinations or blurry vision than would surgical patients, whose postoperative pain is not controlled but who may have other analgesic options.
As noted in the guidelines, the maximum ketamine infusion rate at most of the institutions of the authors, including mine, was 1 mg/kg per hour. When treating acute pain, and particularly perioperative pain, this rate will very rarely be reached. Like most guidelines, this recommendation must be weighed against clinical judgment and experience, so if circumstances dictate, the rate may occasionally exceed 1 mg/kg per hour.
Literature Review Had Some Surprises
During the process of searching the literature and reviewing the relevant studies, it became apparent to me that despite the widely accepted idea that ketamine is effective as an acute pain analgesic for opioid-tolerant patients in particular, only a few studies actually focused on this challenging patient population. Loftus et al10 studied opioid-dependent patients undergoing major spine surgery and reported that patients who received ketamine had better short- and long-term analgesia and less opioid consumption at 6 weeks.
Barreveld et al11 concluded that ketamine had a “limited” benefit for opioid-tolerant patients who underwent various surgeries. At least one negative study was published in spine patients,12although a meta-analysis of spine surgery found that ketamine improved postoperative analgesia for 24 hours.13
Given the role of the N-methyl-D-aspartate (NMDA) receptor in opioid tolerance,14 it makes sense that long-term users of opioids would particularly stand to benefit from an agent like ketamine. I had expected to uncover many studies on this topic with a large number of patients, but the challenge is performing such studies in one of the most notoriously difficult patient groups.
Despite the relatively small number of randomized controlled trials (RCTs) of ketamine in opioid-tolerant patients, the authors of the guidelines universally agreed that it should be considered for all but the most minor of procedures in this patient group. These patients are likely the very ones who gain the most from ketamine’s potent analgesia.
Widespread Adoption Elusive
Widespread adoption of subanesthetic ketamine in hospitalized patients remains an elusive goal. Although the reasons for this failure are not entirely clear, the adverse effect profile certainly plays a role. As an analog of phencyclidine, ketamine has been associated with hallucinations, unpleasant dreams, and dissociative feelings, collectively referred to as psychomimetic effects. These undesirable effects may be likely to occur when ketamine is used as an anesthetic induction agent, as the manufacturer’s label indicates,9 but their incidence when used in subanesthetic doses is less clear.
Some reviews of perioperative subanesthetic ketamine have found that psychomimetic effects do not occur at a frequency greater than with placebo,7,15 whereas others reported an increase in these effects.3,8 There is no universal dose that will cause bothersome effects, and therefore clinical experience and judgment must be relied upon with each individual patient. As noted in the chronic pain guidelines,1 adverse effects are generally dose dependent, but I have observed patients who have experienced hallucinations at 10 mg per hour who required discontinuation of the infusion and others who have tolerated rates of up to 1 mg/kg per hour with minimal complaints. Flexibility is key and close observation is necessary, especially of ketamine-naive patients during the initial titration.
Considerable interest has arisen in the use of nonparenteral forms of ketamine, intranasal (IN) being the most common, for pain exacerbations and procedural sedation. The studies of IN ketamine, as the guidelines pointed out, have been small and largely conducted in the emergency department setting. One important issue to note with IN ketamine is it must be compounded by a pharmacy in accord ance with federal regulations, and therefore finding it can sometimes be a challenge.2 A recommendation of Grade C with low to moderate certainty was made by the committee for the use of IN ketamine in acute pain, meaning that “the [US Preventive Services Task Force] recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.”16
Patients should be offered this treatment on a case-by-case basis. In acute pain in my practice, IN ketamine is almost never used. There may very well be a role for it in the chronic pain setting, however, with its onset of 5 to 10 minutes and duration of 45 to 120 minutes,1 and there is some evidence that it works for patients who have migraine with aura17 as well as neuropathic pain.18
There is potential for IN ketamine to be used for pain exacerbations in between IV ketamine treatments, but this strategy has yet to be studied. Additional studies in the acute pain setting, particularly in the perioperative setting, are needed for IN ketamine to determine what, if any, role this formulation may have.
Contraindications Are Relative
In the acute pain guidelines’ Tables 5 and 6, the contraindications to ketamine are described; all are relative contraindications (Table). This was intentional since, unlike in the setting of anesthesia induction where several alternatives with fewer side effects exist, subanesthetic ketamine may very well have benefits that outweigh potential risks in many situations.
|Table. Summary of ASA/ASRA/AAPM Recommendations for Subanesthetic Ketamine in Acute Pain|
|Recommendation Category||Recommendation||Level of Evidencea|
|Indications for use||
|Dosing range||Bolus: up to 0.35 mg/kg
Infusion: up to 1 mg/kg per hour
|Grade C, moderate certainty|
|Personnel||Supervising clinician: a physician experienced with ketamine (anesthesiologist, critical care physician, pain physician, emergency medicine physician) who is ACLS certified and trained in administering moderate sedation.
Administering clinician: registered nurse or physician assistant who has completed formal training in safe administration of moderate sedation and is ACLS certified.
|Grade A, low certainty|
a Evidence was evaluated according to the US Preventive Services Task Force grading of evidence, which defines levels of evidence based on magnitude and certainty of benefit.
AAPM, American Academy of Pain Medicine; ACLS, advanced cardiovascular life support; ASA, American Society of Anesthesiologists; ASRA, American Society of Regional Anesthesia and Pain Medicine; OSA, obstructive sleep apnea
Reprinted with permission from reference 2.
Many of the relative contraindications in the guidelines are historical in nature and the affected populations have simply not been studied. For example, pregnant patients have been excluded from virtually every study involving ketamine, leaving clinicians with no data to guide treatment decisions. Most of the analyzed studies in the guidelines, including multiple RCTs, listed psychosis as a contraindication. That leaves several questions unanswered, including whether only patients with active psychosis or those with a history of psychosis should also be excluded.
As reported by Lahti et al,19 patients with schizophrenia are at risk for reactivation of symptoms with ketamine use, and in my practice these patients rarely, if ever, receive ketamine. The decision is less clear in other patients, such as those with a history of major depression with psychotic features or isolated episodes of psychosis. Generally, a substantial benefit for patients receiving ketamine should justify its use in a specific population, such as intolerance of other analgesics or pathology that has been shown to improve with ketamine in the literature (eg, complex regional pain syndrome).
Before the publication of the acute and chronic pain consensus guidelines for subanesthetic ketamine, there was no source of recommendations outside of those from individual institutions. The guidelines are inherently limited by the quality of the studies reviewed. In certain areas, prospective studies have simply not been conducted for a variety of reasons, including low disease prevalence, difficulties with enrollment, and the challenging nature of the target population.
Despite these limitations, clinicians now have a blueprint to reference as they adjust or establish a ketamine program. The data presented and summarized in the guidelines can be used to persuade pharmacy and therapeutics committees that ketamine can be used safely and effectively as an alternative or adjunct to opioids at a time when the United States is experiencing a major health crisis involving opioids.
- Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018. doi: 10.1097/AAP.0000000000000808
- Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018. doi: 10.1097/AAP.0000000000000806
- Laskowski K, Stirling A, McKay WP, et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58(10):911-923.
- Craven R. Ketamine. Anaesthesia. 2007;62(suppl 1):48-53.
- Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989;36(2):186-197.
- Schwenk ES, Goldberg SF, Patel RD, et al. Adverse drug effects and preoperative medication factors related to perioperative low-dose ketamine infusions. Reg Anesth Pain Med. 2016;41(4):482-487.
- Bell RF, Dahl JB, Moore RA, et al. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49(10):1405-1428.
- Elia N, Tramer MR. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain. 2005;113(1-2):61-70.
- Clement RC, Bhat SB, Clement ME, et al. Medicare reimbursement and orthopedic surgery: past, present, and future. Curr Rev Musculoskelet Med. 2017;10(2):224-232.
- Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative ppiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639-646.
- Barreveld AM, Correll DJ, Liu X, et al. Ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: results of a prospective, randomized, double-blind study. Pain Med. 2013;14(6):925-934.
- Subramaniam K, Akhouri V, Glazer PA, et al. Intra- and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake. Pain Med.2011;12(8):1276-1283.
- Pendi A, Field R, Farhan SD, et al. Perioperative ketamine for analgesia in spine surgery: a meta-analysis of randomized controlled trials. Spine (Phila Pa 1976). 2018;43(5):E299-E307.
- Elliott K, Minami N, Kolesnikov YA, et al. The NMDA receptor antagonists, LY274614 and M&801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids.Pain. 1994;56(1):69-75.
- Jouguelet-Lacoste J, LaColla L, Schilling D, et al. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med. 2015;16(2):383-403.
- US Preventive Services Task Force. Grade definitions. www.uspreventiveservicestaskforce.org/ Page/ Name/ grade-definitions. Accessed July 1, 2018.
- Afridi SK, Giffin NJ, Kaube H, et al. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.Neurology. 2013;80(7):642-647.
- Rigo FK, Trevisan G, Godoy MC, et al. Management of neuropathic chronic pain with methadone combined with ketamine: a randomized, double blind, active-controlled clinical trial. Pain Physician. 2017;20(3):207-215.
- Lahti AC, Holcomb HH, Medoff DR, et al. Ketamine activates psychosis and alters limbic blood flow in schizophrenia.Neuroreport. 1995;6(6):869-872.