The opioid epidemic has captured the attention of all the leading medical organizations in the country, including the American Medical Association, American Society of Regional Anesthesia, and the American Society of Anesthesiologists. The Surgeon General recently wrote a letter to all physicians in the United States, imploring us to educate ourselves, screen our patients, and commit to fixing the problem.¹ Alternatives to opioids or techniques that markedly reduce opioids are highly desirable. Ketamine, an N-methyl-D-aspartate receptor antagonist, has emerged as such a drug because of its potent analgesia and lack of respiratory depression. Low-dose (subanesthetic) ketamine infusions can improve postoperative pain and decrease opioid consumption with the greatest benefit occurring during the most painful surgeries.² There is likely some benefit even from an intraoperative infusion alone with a preincision bolus.³ Although more studies are clearly needed, persistent postsurgical pain may also be decreased through the use of intravenous (IV) ketamine.⁴ 

At Thomas Jefferson University Hospital (TJUH) under the direction of Dr Eugene Viscusi, we have had extensive experience with low-dose ketamine infusions on general medical floors for more than 15 years. Although they were initially used primarily for opioid tolerant patients, their versatility and benefits have been recognized over time. We now use ketamine infusions for patients with sickle cell crisis, refractory migraine headaches, and chronic regional pain syndrome (CRPS) and for patients receiving extracorporeal membrane oxygenation (ECMO), in addition to our large opioid-tolerant and opioid abuse populations. Within our clinical guidelines that require involvement of the acute pain management service physicians, residents, and trained nurses, ketamine may be safely administered without intensive care or telemetry monitoring with careful adherence to the protocol and with experienced individuals immediately available. We recently published our experience with perioperative ketamine and reported that patients who received ketamine at TJUH were more likely to be female, younger, undergoing more complex surgery, and were more frequently opioid-tolerant (especially taking scheduled opioids).⁵

Ketamine’s adverse-effects profile from its use as an anesthetic agent has received much attention and is one of the primary reasons cited for reluctance to use it, despite numerous reports of its safety. Ketamine rarely causes respiratory depression.⁶ Of bigger concern for most clinicians is the potential for central nervous system (CNS) side effects. Two randomized, controlled trials^7-8 that compared low-dose postoperative ketamine infusions to placebo found no statistical difference between groups regarding CNS adverse effects, including hallucinations and confusion, as well as nausea, vomiting, and diplopia. Our experience at TJUH expands upon this and includes nonsurgical patients as well as surgical patients and reflects clinical practice in an experienced center. Less than a third of the patients in our sample (n = 321) experienced any adverse drug effects. Infusion had to be stopped in only one-third of those who experienced adverse effects owing to their severity.⁵ Although CNS excitation was the most common adverse drug effect, it still only affected 16.2% of patients, two-thirds of which did not require discontinuation of the infusion. Typically, for milder adverse drug effects, such as a single episode of a vivid dream, treatment might include a benzodiazepine such as lorazepam 0.5–1 mg IV and a decrease in the infusion rate by 5–10 mg/hr.

Although we do start ketamine infusions postoperatively on a frequent basis, the ideal time to initiate them is intraoperatively with consideration of a preoperative bolus. Loftus et al³ demonstrated a clear analgesic benefit to intraoperative ketamine, and our experience has shown us that starting the infusion in the operating room (OR) or soon after arrival to the recovery room provides better analgesia than waiting until the evening after surgery or later. This allows for dose adjustments to be made before the patient goes to his or her room on the medical ward and ensures that adjunctive medications, including opioids, benzodiazepines, and a clonidine patch, are ordered in appropriate doses. From time to time, a few surgeons prefer that their patients not receive postoperative ketamine and, in these patients, there is likely still a benefit for intraoperative ketamine. Although ultimately the starting infusion rate is at the discretion of the anesthesia team in the OR, we typically recommend a bolus of 0.5 mg/kg and an infusion starting rate of 0.25 mg/kg/hr, which is a rate that typically achieves a balance between analgesia and adverse effects.

When adjusting infusions for patients in the postoperative period, several factors should be considered. The patient’s age, weight, pain level, and previous experience with ketamine, if any, should all be weighed into the decision. Smaller patients who have never received ketamine previously, for example, might get a rate increase of 5 mg/hr for an increase in pain, while a large patient who has been followed up by the acute pain service previously, and received ketamine without problems, might have the rate increased by 10–15 mg/hr at a time. As previously mentioned, guidelines are imperative for a successful program. We do not allow nurses to administer ketamine boluses, for example; this must be done by a resident or attending physician.

We have also observed several hundred patients with intractable migraine headaches report substantial improvement in their headache intensity after undergoing a multiday course of a ketamine infusion. Infusion rates are aggressively titrated with a soft upper limit of 1 mg/kg/hr and the presence of adverse effects as the only constraints. We work closely with our neurology colleagues, who help coordinate the admission and care of these complex patients. These patients do not require intensive care or telemetry monitoring within the established protocols we have in place. Ketamine infusion rates are often more aggressively titrated in this population to achieve analgesia faster. Other special groups of patients for whom we manage ketamine infusions include those with CRPS, many of whom have failed most other therapies, and patients who are mechanically ventilated on ECMO. In many cases, ketamine has allowed for much lower rates of opioid infusions and facilitated earlier extubation.

In summary, ketamine is a drug with multiple uses, both in the perioperative period and outside the OR environment. No drug is without side effects. In our experience, the side effects of ketamine have been very well tolerated, particularly when compared to the risks associated with high-dose opioids. If used in the context of a protocol that sets clear rules and includes training of staff members, it can be very effective and safe.

References    

1. Murthy V. The Surgeon General’s call to end the opioid crisis. Available at: turnthetiderx.org. Accessed September 22, 2016.

2. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anesth 2011;58:911–923.

3. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 2010;113:639–646.

4. McNicol ED, Schumann R, Haroutounian S. A systematic review and metaanalysis of ketamine for the prevention of persisten post-surgical pain. Acta Anaesthesiol Scand 2014;58:1199–1213.

5. Schwenk ES, Goldberg SF, Patel RD, et al. Adverse drug effects and preoperative medications factors related to perioperative low-dose ketamine infusions. Reg Anesth Pain Med 2016;41:482–487.

6. Craven R. Ketamine. Anaesthesia 2007;62:48–53.

7. 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;12:1276–1283.

8. Garg N, Panda NB, Gandhi KA, et al. Comparison of small dose ketamine and dexmedetomidine infusion for postoperative analgesia in spine surgery: a prospective randomized double-blind placebo controlled study. J Neurosurg Anesthesiol 2015;28:27–31.