Does Ketamine Improve Postoperative Analgesia? More Questions Than Answers

Our unit found that the use of ketamine as an anesthetic to be extremely beneficial when faced with a large number of casualties, and a limited amount of medical supplies… . patients did not require intubation, or any supplemental oxygen. We saved our meager stocks of medical supplies such as endotracheal tubes, anesthesia circuits and cylinders of oxygen. We also saved OR time…. MAJ Mark Meeks, MD 86th Combat Support Hospital, Operation Iraqi Freedom 2003 In the last decade, there has been a resurgence of ketamine use both in the military medicine and in the civilian setting. Discovered in 1962, ketamine was officially released for clinical use in 1970 as an anesthetic but quickly developed a bad reputation when military physicians in Vietnam and others reported severe adverse effects including psychotomimetic phenomenon. For over 30 years, ketamine was relegated to use only for the induction of anesthesia in special circumstances including hypotensive patients and those suffering severe asthma or chronic obstructive pulmonary disease (COPD) exacerbations. Only recently did authors debunk several myths attributable to ketamine including the degree of emergence reactions, hallucinations, elevations of intracranial pressure, and lowering seizure threshold 1,2. The resurgence of use is likely related to this and several other potentially advantageous factors. For example, ketamine is versatile and can be administered through multiple routes including oral, rectal, nasal, intravenous, intramuscular, epidural, or intrathecal. Ketamine also possesses most of the characteristics of an ideal anesthetic including a dose-dependent effect to produce analgesia, amnesia, loss of consciousness, suppression of the stress response, and akinesia. Moreover, with respect to analgesia, ketamine has been found to effect both the central and peripheral receptors including N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-1-4-isoxazole propionate, kinate, and γ-aminobutyric acid A receptors. Ketamine also inhibits serotonin and dopamine uptake, nitric oxide pathways, and µ-opioid receptors. As a result of these multiple receptor actions, researchers have demonstrated that ketamine can effectively reduce allodynia, hyperalgesia, hyperpathia, and opioid tolerance. Interestingly ketamine has come to full circle and, subsequently, found its way back on the battlefield, used extensively by the US military for the last 8 years as an anesthetic and adjunct for patients with chronic pain due to devastating complex polytrauma. Ketamine, used in subanesthetic doses, has also recently been used as an adjuvant to opioids in the treatment of acute postoperative pain, and some experts propose that it may also be useful to reduce chronic postoperative pain by reducing wind up and central sensitization. Several systematic reviews of ketamine for postoperative pain demonstrated clear decreases in cumulative morphine equivalents and up to a 50% reduction of rescue analgesics 3. Furthermore, the adverse psychotomimetic effects responsible for giving ketamine a bad name in the 1970s were mild or absent 3. Because of these impressive results, some have suggested that perioperative ketamine may be useful in groups of patients who are treated with long-term or high-dose opioids. These patients frequently require increased doses of opioids to control postoperative pain with increased risk of postoperative cardiopulmonary and gastrointestinal dysfunction. The goal of finding methods to improve pain control in these patients while minimizing opioid related adverse effects and improving outcomes is worthy of investigation. Unfortunately, little data except anecdote, case reports, or small series exist regarding these difficult to manage patient groups. One recent randomized, prospective double-blind, placebo-controlled trial in opiate-dependent patients undergoing major lumbar spine surgery compared 52 patients administered 0.5 mg/kg intravenously at induction and 10 ug/kg/min infusion until wound closure with 50 patients administered saline 4. The authors demonstrated a significant reduction in postoperative opiate consumption in the first 48 hours although pain scores were similar 4. Interestingly, the ketamine-treated patients reported significant reductions in pain at 6 weeks with a decrease in opiate consumption of 71% 4. The effect was most pronounced in patients receiving higher doses of opiates preoperatively 4. The use of ketamine was safe and without increased in adverse effects. In this edition of Pain Medicine, Subramaniam and colleagues have also tried to take on this subject in a scientific way. They report the first prospective, randomized, double-blinded and placebo-controlled clinical trial investigating the efficacy of low-dose intravenous (IV) ketamine infusion continued for 24 hours postoperatively in patients exposed to preoperative opioids undergoing major spine surgery 5. The study evaluated the use of ketamine at induction in a dose of 0.15 mg/kg and an infusion of 2 ug/kg/min for 24 hours postoperatively vs saline bolus and saline infusion. All patients were also treated with a hydromorphone patient-controlled analgesia (PCA) and surgically placed epidural with bupivacaine infusion, although only 53–60% of the patients had a functional epidural. The primary endpoints of the study were PCA use, pain control, and ketamine side effects, evaluated for the first 48 hours postoperatively. This study is well designed, and the authors concluded that the addition of very low dose IV ketamine infusion does not improve postoperative analgesia in these patients. I think the conclusion of this study is accurate; however, it leads me to question, why not? The authors performed a power analysis for a 30% decrease in hydromorphone consumption, noting a requirement of 26 patients in each group. They did not base their analysis on the critical endpoint of change in pain scores. This analysis would have required hundreds of patients to detect a statistically significant difference in pain scores. Using opioid consumption could be a significant confounder as many patients may have required the hydromorphone to treat their withdrawal rather than for pain purposes. While opioid consumption is commonly used as a surrogate for analgesia, the alterations in pharmacodynamics/kinetics seen in patients postoperatively make this endpoint dubious. Moreover, the authors stopped the study after 38 total patients due to feelings by the clinicians and pain teams that there was no difference in the quality of analgesia, while they felt there were increased side effects using the study drug over their standard practice. Unexpectedly the authors found out that, in fact, adverse effects were higher in the saline placebo control group. Ending a study for safety reasons is legitimate, although discontinuance based on feeling erodes the scientific nature of the endeavor and also affected the ability to enter enough patients in order to find real differences. The large ranges of visual analog scale (VAS) scores in some cases exceeding over 50% of the total are skewed toward the average, which make meaningful comparisons difficult. The authors did not attempt to describe individually or control for the amount of preoperative opioids or adjunctive pain medications taken by the study patients. They did however identify that preoperative VAS scores were similar between groups. Unfortunately, this comparison does little to compare individual opioid requirements postoperatively. Additionally, the wide variations in intravenous patient-controlled analgesia (IVPCA) hydromorphone consumption are also a concern with respect to individual patient requirements. Reported as a mean, statistically, only few individuals can significantly skew the results. Ultimately, these problems make it difficult to draw any significant conclusions about this study except that ketamine in these very low doses appeared safe and without increased side effects compared with saline placebo. The discordance from the Loftus study raises lingering questions. It is likely however that one size or dose does not fit all patients. For example, the Loftus study demonstrated that patients with higher preoperative opioid doses may benefit more. They also used considerably larger intraoperative doses. Based on these studies, it is still difficult to know whether ketamine is truly effective in these patients. The residual and unanswered questions also include the following: 1) Is there an effect of higher doses perioperatively/postoperatively?; 2) At what point do higher subanesthetic doses increase side effects without accruing benefit?; 3) Is there a role for S-ketamine?; 4) Should doses be tailored to adjust for preoperative opioid requirements or higher preoperative VAS scores?; and 5) Does ketamine improve functional outcomes or longer term pain control? Despite these questions ketamine has stood the test of time and proven itself to be a versatile and useful anesthetic and analgesic in the right doses and right patients with minimal side effects. Its role in patients on preoperative opioids, however, is less clear, and many questions require rigorous scientific investigation to be definitively answered.