Blog with interesting cases and/or problems related to anesthesia with discussion based on best evidence in the literature.

June 1, 2008

Ketamine for the reduction of both acute and chronic post operative pain

A 54 year old female comes to the OR for an open hemicolectomy. The patient is offered a thoracic epidural for post op pain control. Is there another medication that might be considered to reduce her acute post operative pain scores? Is there any merit to aggressive treatment of her post op pain in hopes of reducing her chance of developing chronic post surgical pain?

After major abdominal and thoracic surgery, it is now well accepted that aggressive treatment of acute post operative pain is important and may enhance recovery to some degree. What is less well recognized and even less well understood is the relationship of acute post op pain to the development of chronic post surgical pain. The incidence of the development of chronic post surgical pain is unclear and varies from surgery to surgery. What is clear however is that multimodal analgesia is preferred in the acute setting and may be beneficial in reducing chronic pain as well.
Major abdominal surgery, like thoracic surgery, can result in significant post operative pain in the first 3 to 4 days after surgery. In a small subset of patients, there is a risk of developing a chronic post surgical pain syndrome resembling in some ways neuropathic pain. Although there are no criteria that can allow easy prediction of those patients who will go on to develop chronic post surgical pain, it has been demonstrated that those patients who have a greater degree of primary and secondary hyperalgesia after surgery are at higher risk. In a paper on the epidemiology of chronic pain, Visser EJ noted that wound hyperalgesia (which suggests central sensitization) correlated better with chronic pain after 6 months than did acute post operative pain (R=0.81)[1] In other types of surgeries, (mastectomy, thoracotomy and inguinal hernia repair), there is tight correlation between acute and chronic pain. In either case, it is likely that central sensitzation plays a critical role in the development of chronic post surgical pain. Neuronal blockade with local anesthetics are one very effective way to mitigate the development of central sensitzation; but for many patients this is not an option. Ketamine, on the other hand, is inexpensive, readily available in most operating room settings, and in low doses, can be given with relatively few side effects. So is there any benefit in administering ketamine to our patients? In theory, it should. It is known that ketamine acts as an NMDA antagonist, and the NMDA receptor is a major player in central sensitization. In fact, Ilkjaer S et al. demonstrated in a clinical trial with 19 volunteers that ketamine does in fact reduce hyperaglesia (marker for central sensitization) when given in a dosage of 0.3 mg/kg with minimal side effects[2]. There are numerous studies in animal models in which ketamine has also demonstrated the prevention and even reversal of both injury induced hyperalgesia and opioid induced hyperalgesia. In clinical trials with pain as an outcome, ketamine has demonstrated good effect although to a lesser degree than would be expected based on animal models. Likely reasons for this include the fact that ketamine binds to many other receptors (opioid, cholinergic, Na channels and voltage sensitive Ca2+ channels). Furthermore, the NMDA receptor is not the only mediator of central sensitization and chronic pain. Other receptors/pathways include Cox-2, Alpha 2 delta subunit of Ca2+ channels, AMPA receptors, NOS, dynorphin and hemoxygenase.
Neverthless there are several important RCTs that have demonstrated that even at low dosages, ketamine can play a small role in the reduction of chronic and acute pain. One of the most striking studies was done by Marc De Kock, Patricia Lavand'homme and Hilde Waterloos[3]. They had 5 groups of patients in which each group underwent major abdominal surgery for rectal adenocarcinoma and all patients were giving an epidural with bupivacaine, clonidine and sufenta for pain control. Group 1 was placebo, Group 2 was given a bolus of ketamine of 0.25mg/kg and then an infusion for the duration of surgery of 0.125 mg/kg/hr. Group 3 was given double the dose of group 2 and groups 4 and 5 were given respectively the same ketamine doses as groups 2 and 3, but the ketamine was administered epidurally. Pain scores at rest and during mobilization were not statistically different for the first 48 hours after surgery, although, morphine use was statically less in group 3 (IV ketamine at 0.5 mg/kg + 0.25mg/kg/hr infusion) at 48 hours. The authors also measure the area of hyperalgesia around the wound as an indicator of the degree of central sensitization suffered by the patients which correlates with the development of chronic post surgical pain. They found that the area of central sensitization was statiscally significant only in group 3 (ketamine IV at 0.5 mg/kg bolus + 0.25 mg/kg/hr infusion). the authors then followed up with the patients in each group to measure residual pain at 2 weeks, 1 month and 6 months. Once again the number of patients with residual pain was statistically less only in group 3. The take home message from this RCT is that ketamine should be given IV (not neuraxially) and at the appropriate dosage to realize the benefits of reduced chronic post surgical pain. More importantly, ketamine was shown to be effective despite that patients were given epidurals for post op pain control. Stubhaug A et al. also found that ketamine can decrease the degree of central sensitization after abdominal surgery[4]. They performed a DB RCT with 20 living kidney donors. Once group received ketamine as a bolus prior to incision of 0.5 mg/kg (same as the De Kock study) followed by an infusion of 0.12 mg/kg/hr x 24 hr, then reduced to 0.06 mg/kg/hr x 48 hr. They found that the area of hyperalgesia was less on days 1, 3, and 7 after surgery in those patients given ketamine. Unfortunately they did not follow up patients at later time periods in order to measure the incidence of chronic post surgical pain.

Ketamine also can play a role in thoracic surgery whether patients are treated with an epidural or not. Perkins and colleagues did an analysis of the incidence of chronic pain after thoracotomy and found that an outstanding 47% had chronic pain. In their analysis, they did find that acute pain after surgery did predict those that went on to develop chronic pain. Neuraxial analgesia in the perioperative period has been shown to reduce the incidence of both acute and chronic pain [5,6]. However, despite the use of epidural analgesia for post thoracotomy pain, there are individuals who do have problematic acute pain and chronic pain. In other instances, thoracic epidural analgesia is contraindicated. Therefore, Ketamine can be a useful adjuvant for the anesthesiologist who gives priority to reducing the incidence of chronic post surgical pain. Evidence for this comes to us from a few studies. Chow and colleagues [7] found in a DB, RCT of 14 patients undergoing thoracotomy that patients receiving ketamine vs. morphine only had lower VAS scores at 6, 24, and 48 hrs as well as upto 56% less morphine requirements. Furthermore, at 2 months the patients who had received ketamine had less symptoms of chronic pain on the McGill Pain Questionnaire and decreased hyperalgesia indicating suppression of central sensitization. The ketamine dose was 0.15 mg/kg/hr for 3 days. Increased side effects were not found in the ketamine group to be statistically significant. In another study published in Anesthesiology [8] in 2006 found that ketamine added to patients already receiving epidural anesthesia for open thoracotomy was beneficial. Ketamine was titrated to maintain plasma concentrations of only 20 ng/mL over a 3 day period. The initial dose was 0.05 mg/kg/hr (very small). Patients who received ketamine in addition to thoracic epidural reported lower pain scores at 48 hrs, 1 week, 1 month and 3 months after surgery.

It seems that there is reasonable evidence that it might be prudent to utilized ketamine in small dosages in certain patients (probably those not suffering from dementia or at risk of acute delirium in the hospital) to prevent the development of chronic post surgical pain. Major open abdominal surgery, reconstructive breast surgery and thoracic surgery are most likely to result in chronic pain syndrome. However, the utilization of ketamine to prevent or mitigate acute post operative pain may also be helpful. Three large reviews/meta analyses [9,10, 11]have been published on ketamine. They included a large number of studies and comprised a variety of different surgeries. The first, a large systematic reivew by Subramaniam K et al. concluded that ketamine was a safe and useful adjuvant to standard practice opioid analgesia. The second, another systematic review of 24 articles looking for evidence of preventive analgesia (i.e. Pain control lasting longer than expected based on the pharmakokinetics of the medication) concluded: Ketamine provided additive pain control immediately and beyond the expected clinical action of the drug. The authors theorized that ketamines preventive analgesic characteristics resulted from its ability to prevent central sensitization. Thirdly, Himmeslseher S et al. published a meta analysis on ketamine. They concluded that subanesthetic ketamine used during GA provides pain prevention in the post op period and made the following recommendations:
1) Major surgery: give bolus prior to incision of 0.5 mg/kg followed by infusion of 0.5 mg/kg/hr during surgery and then reduce to 0.12 mg/kg/hr x 24 hrs after surgery.
2) Minor surgery: bolus of 0.25 mg/kg then 0.25 mg/kg/hr during surgery.

In conclusion, I consider ketamine for all major abdominal, thoracic and even orthopedic surgeries where I expect pain to be severe. I consider ketamine to be a one modality of pain control in a large possible reperatoire of interventions (NSAIDs, local anesthetics, opioids, Alpha 2 agonists). I avoid or use smaller doses of ketamine in elderly patients ~70 and up, or in any patient with significant psychiatric disease. I also discontinue ketamine use within 45 min of the end of surgery or even 1 to 2 hours for prolonged surgical cases (4 to 6 hours). Anesthesiologists often don't follow their patients for 1 year after surgery to see whether they develop chronic pain, and therefore often do not consider possible interventions to mitigate this risk. Nevertheless, in a small subset of patients, the modalities of pain control we utilize will potentially effect outcomes up to a year in the future. Therefore, it is incumbent upon us to be abreast of the literature on post op pain control, chronic post surgical pain syndromes and the possible preventive measures available to us.

[1] Visser EJ. Chronic post-surgical pain: Epidemiology and clinical implications for acute pain management. Acute Pain; 8(2) 2006: 73-81.

[2] Ilkjaer S et al. Effect of systemic NMDA receptor antagonist (ketamine) on primary and secondary hyperaglesia in humans. BJA. 1996; 76: 829.

[3] De Kock M, Lavand'homme P, Waterloos H. Balanced analgesia in the perioperative period: is there a place for ketamine? Pain 92(2001) 373-380.

[4] stubhaug A, Breivik H, Eide PK,Kreunen M and Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41: 1124-1132.

[5] Obata H, Saito S, Fujita N, et al. Epidural block with mepivacaine before surgery reduces long-term post thoracotomy pain. Can J Anaesth 1999;46:1127-32.

[6] sentruk M, Ozcan PE, talu GK, Kiyan E, Camci E, Ozyalcin S, Dilgege S, Pembeci K: the effects of three different analgesia techniques on long-term postthoracotomy pain. Anesth Analg 2002;94:11-5.

[7] Chow TKF, Goodchild CS, Shanahan EA, O'Flaherty M, NMcNeil JJ. Adding ketamine to morphine reduces acute and chronic post-thoracotomy pain. Anaesth Intens Care 2002; 30:692-3.

[8] Suzuki M, Haraquiti S, Sugimoto K, Kikutani T, shimada Y, Sakamoto A. Low dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006 Jul: 105(1): 111-9.

[9] Subramaniam K, Subramaniam b, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic reivew. Anesth Analg 2004;99:482-95.

[10] McCartney CJ, Sinha A, Katz J. A Qualitative systematic Review of the role of NMDA receptor antagonists in Preventive Analgesia. Anesth Analg. 2004; 98: 1385-400.

[11] Himmeslseher S, durieux ME. Ketamine for perioperative Pain Management. Anesthesiology. 2005; (102):211-20.

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