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Ketamine: Teaching an Old Dog New Tricks?

INTRODUCTION
Ketamine is a drug that has been around for a long, long time. In many ways, it is a drug that provides a "complete" anesthetic in that it combines sedation, amnesia and pain relief. At the same time, it has less tendency to depress airway reflexes than some of the other commonly used anesthetic agents. Ketamine certainly still has some appropriate uses in modern anesthetic practice, however it seems to have fallen out of favor for everyday use.

Some of this certainly has to do with the development of newer agents with less side effects. Ketamine is well known to increase heart rate, increase blood pressure, increase secretions, etc. In addition, as a drug in the same class as the street drug PCP, it is well known to cause hallucinations and nightmares in some settings. Lastly, ketamine seems to have gained some stigma because of its common use in veterinary medicine.

This article is not intended as a discussion of all the properties of ketamine. Nor is it intended to argue for or against its place in the delivery of anesthesia today. However, what is clear is that ketamine is finding some possible uses today that might mean that there will be future "niche" uses for this drug that we have had so long.

ANALGESIC ADJUVANT/PRE-EMPTIVE ANALGESIA?
It has always been clear that ketamine provides analgesia via a different mechanism when compared to opioids. More and more evidence is piling up that this action on NMDA has beneficial effects. For example, it is a common observation clinically that some patients have pain that is resistant to opioids. There is some evidence to suggest that this resistance is the result of the activation of NMDA receptors in the perioperative period.

A recent study (Weinbroum, Avi A. Anesth Analg 2003; 96:789-95) shows ketamine in low dose is an effective adjunct for analgesia in these patients. The study also showed that there was a lack of significant side effects at the low doses given. What is interesting is that they found that the effects of low dose ketamine lasted past the known plasma half-life of ketamine. This suggests that ketamine may play a role in preventing opioid tolerance and reducing central sensitization in the face of pain.

Similar findings have been reported elsewhere. The postulation that ketamine can provide analgesia while at the same time inhibiting NMDA activation (that might then prevent central sensitization and future hyperalgesia) is an active area of interest for many current researchers. Early results are promising - but much work remains to be done.

What is clear, however, is that low dose ketamine can help with analgesia while not increasing the side effect profile. It can be used for this purpose even without the findings of additional long-term benefit. If it also might have beneficial effects in terms of pre-emptive analgesia, that would be an interesting finding indeed.

ADJUNCT IN PERIPHERAL BLOCKADE
Low dose ketamine also appears to be a useful adjunct when the primary form of pain relief is peripheral nerve block. A recent abstract presented at the American Society of Regional Anesthesia meeting (2003 meeting, abstract A4) showed that ketamine added to local anesthetic for interscalene block was beneficial. Indeed, the combination of these two drugs provided pain relief for shoulder surgery beyond the duration of either the ketamine or the local anesthetic.

Specifically, the need for supplemental morphine was reduced from eight hours post-operatively all the way to sixteen hours post-operatively. The study was did not follow patients past sixteen hours. This opioid sparing effect lasted much longer than the half life of ketamine, which is about three hours. This finding again implies some mechanism by which ketamine affects central sensitization to pain.

Whether or not ketamine added to other types of peripheral nerve block for other types of surgery is effective remains to be seen. Also, the optimal dose of ketamine as an adjunct to peripheral nerve block is unknown. However, the suggestion that a very low dose of ketamine (low enough to avoid side effects) might have significant implications for post-operative care is once again intriguing.

Ketamine may have lost favor as a primary anesthetic agent in most cases. Its side effect profile can be problematic and is something that anesthesiologists should be aware of if they choose to use this drug. However, it seems that low doses, low enough to avoid side effects, may be finding a role in the treatment of postoperative pain by both intravenous methods and peripheral nerve blocks. In addition, ketamine may turn out to provide some significant benefits in terms of pre-emptive analgesia and the ability to prevent NMDA activation in the perioperative period.

It seems that we are indeed "teaching an old dog new tricks" and it will be interesting to follow the research about this topic as it evolves.


 

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