Timothy Lubenow, MD
Anthony Kirkpatrick, MD, PhD
University of South Florida
Barry Friedberg, MD
University of Southern California
Los Angeles, California
TREATMENT WITH KETAMINE:
Ketamine infusions have been reported to be safe and efficacious for the management of refractory complex regional pain syndromes (CRPS) in both the inpatient  and outpatient  settings. This therapeutic intervention can be especially helpful in the emergency room setting where large doses of narcotics (opioids) are often injected to control pain. The problem with narcotics is that huge doses are required because the neuropathic pain caused by CRPS is relatively resistant to the pain-relieving effects of narcotics. The use of narcotics often leads to hospitalization of the patient due to prolonged heavy sedation and respiratory depression. In addition, chronic use of narcotics leads to physical dependency, tolerance and constipation.
In contrast, ketamine has a very selective effect on relieving pain due to CRPS without causing prolonged sedation and respiratory depression. Therefore, ketamine is less likely to lead to lengthy and expensive hospitalizations. There is no problem with physical dependency, tolerance or constipation with ketamine.
In addition, ketamine "booster" infusions have proven effective in patients with severe, multiple extremity, intractable, CRPS. Most of these patients have failed all reasonable treatment options for CRPS. Ketamine booster infusions are likely to lead to fewer emergency room visits for these extremely difficult and serious cases of CRPS. The FDA-approved drug insert supports the safety ketamine:
"Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to ten times that usually required) have been followed by prolonged but complete recovery.”
The merits of using ketamine over narcotics to treat CRPS were presented at an international symposium held at the University of South Florida:
Use of Opioids (Narcotics) to treat RSD / CRPS in Adults and Children
A recent lead article in the journal Anesthesiology noted that low dose IV ketamine in combination with an epidural had a significant reduction (p<0.05) in not just acute pain, but it eliminated chronic postsurgical pain one year later.  Therefore, ketamine may play a role role in preventing CRPS following surgery.
Chronic, intractable CRPS is often associated with major depression. A recent randomized trial showed that ketamine has a significant antidepressant effect. Using a single low dose infusion of ketamine for 40 minutes these investigators showed a rapid and prolonged response in treating major depression.  The authors commented:
“To our knowledge, there has never been a report of any other drug or somatic treatment (ie, sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone, or electroconvulsive therapy) that results in such a dramatic rapid and prolonged response with a single administration.”
Resurgence of ketamine
Ketamine is undergoing resurgence. For decades, anesthesiologists used ketamine for induction of general anesthesia at 2 mg/kg. However, some patients hallucinated and the use of the drug waned. We are beginning to see a resurgence using small, low-dose ketamine. Low doses inhibit the NMDA receptors, which is responsible for central sensitization, and can work synergistically with many other analgesics. Hallucinations are extremely rare with low doses of subanesthestic ketamine of about 20 to 40 mg in the average adult. Furthermore, the risk of hallucinations declines with repeated use of ketamine.
TYPICAL KETAMINE INFUSION:
Ketamine Treatment Protocol
The ketamine infusion treatment protocol consists of deep conscious sedation with ketamine. Typically, pretreatment with 0.2 mg of glycopyrolate IV is the only other drug necessary.
A ketamine drip is administered at an escalating dose while monitoring the patient's vital signs and level on consciousness. Typically, a starting dose might be 60 mg / hour and followed by increasing the dose 50% at regular intervals. Midazolam is usually not necessary. However, bad dreams (hallucinations) can occur in patients with RSD / CRPS during the ketamine infusion. These hallucinations can be treated with increment doses of 1-2 mg midazolam IV.
Some patients will obtain relief of pain at a lower infusion rate of ketamine (10-30 mg/hour)
SEE 7-MINUTE VIDEO BELOW
It is important to recognize that the elimination half-life for ketamine is 3-5 hours. Accordingly, it may take 4 half-lives (at least 12 hours) to reach a steady-state (or peak) blood level.  Therefore, initial titration with loading doses are sometimes required to obtain adequate adequate depth of anesthesia during the early phase of the infusion. Incremental doses are added until the desired effect is achieved such as signs of mental dissociation such as inability to answer at set of five simple questions like: "What is your husband's name". (See "SPECIAL CONSIDERATIONS" #1 below regarding adequate anesthesia for a low-dose infusion)
If necessary, keep the mouth dry with glycopyrolate (Robinol 0.1 - 0.2 mg IV doses) and/or suction. This treatment can easily take place in the PACU with a significant other by the bedside to re-assure the patient.
Routine monitoring for these patients typically includes level of consciousness, BP, heart rate and pulse oximetry.
Midazolam (Versed) might not be necessary to counteract the hallucinogenic effects of ketamine in patients with RSD / CRPS. If unpleasant hallucinogenic effects occur with ketamine, 1 to 2 mg of IV midazolam should be given just prior to the ketamine infusion.
During recent years, it has become increasingly clear that long-term or escalating opioid use does not lead to improvement of function in every patient. Case studies of pain report that opioids actually increase pain in some patients as a consequence of injury or surgery, often associated with a modification of the pain character and an extension of the affected region that may persist for days, weeks, or even years.
Use of Opioids .... Learn More
1. Adequate anesthesia for ketamine infusion is not achieved until a patient achieves a state of "dissociation" from external stimulation. A convenient way to test for dissociative anesthesia is to ask a simple question like: What is your name or what city do you live in? If the patient answers "what?", the depth of anesthesia might be too much and require a temporary decrease in dose.
The anesthetic state is termed "dissociative" because it has been suggested that there is a functional and an electrophysiologic "dissociation" between the thalamus and the limbic systems. This dissociative state is very difficult to relate to traditional signs of general anesthesia: thus, nystagmus (eye jerks) and myoclonic movements (body jerks) seen with ketamine make it a challenge to judge the depth of anesthesia at any particular point.
The purpose of this video is to make it easier for physicians to carry out the ketamine infusions where the patient lives. Physicians have used ketamine for decades but they may not be familiar with titrating the dose of ketamine when used in this manner. The video presents the depth of anesthesia from ketamine at three different dose levels: low, medium and high dose.
To view a video presentation of the dose response to ketamine:
7 minute, Broadband video, 340K
7 minute, Broadband video, 150K
7 minute, Dial-up video, 38K
2. Patients prone to nausea with general anesthesia, should receive a prophylactic 4-8 mg of Zofran (ondansetron) p.o. 1-2 hour prior to the low-dose ketamine infusion. The dose of Zofran can be repeated every 8 hours as needed.
Four Case Reports With Video
1. Correll GE, Maleki J, Gracely EJ, et al.
Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to CRPS.
Pain Med 2004; 5:263-75
2. Goldberg ME, Domsky R, Scaringe D, et al.
Multi-day low dose ketamine infusion for the treatment of CRPS.
Pain Physician 2005; 8:175-9
3. Lavand’homme P, DeKock M, Waterloos H.
Intraoperative epidural analgesia combined with ketamine provides effective preventative analgesia in patients undergoing major digestive surgery.
Anesthesiology 2005; 103:813-20
4. Zarate CA, Jr, Singh JB, Carlson PJ, Brutsche NE.
Arch Gen Psychiatry 2006; 63:856-864
Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury
British Journal of Anaesthesia, 2003, Vol. 90, No. 2 155-160