Ketamine in perioperative analgesia for knee surgeries: Review of evidence from randomized controlled trials

Successful perioperative analgesia for knee surgeries results in improved patient satisfaction and promotes successful rehabilitation. However, effective perioperative pain control is commonly a challenging task for knee surgeries. Such surgical procedures as total knee replacement or knee arthroscopy may be accompanied by severe postoperative pain. As opioids and nonsteroidal anti-inflammatory drugs are commonly used, the side effects of these types of medicines are quite common as well, especially in patients with chronic pain, as they are commonly dissatisfied with regular analgesia. Patients with chronic pain tend to have lower tolerance to pain, and be dependent and tolerant to opioids. These patients typically require higher doses of analgesics, which further negatively affect patients’ safety and the overall perioperative experience. Multimodal perioperative analgesia helps to spare opioids and promote successful rehabilitation. Ketamine is a noncompetitive N-Methyl-d-aspartate (NMDA) receptor antagonist that has been used for multimodal perioperative analgesia as an adjunct to opioids and nonsteroidal anti-inflammatory drugs. Despite the significant number of papers evaluating the role of ketamine in perioperative analgesia, the feasibility of ketamine for perioperative pain control in knee surgeries remains a subject of debate. There are only a limited number of high-quality studies on the topic. We used a systematic approach to evaluate randomized controlled trials with perioperative ketamine used for knee surgeries. The majority of the studies confirmed that the utilization of ketamine in perioperative analgesia was associated with lower pain scores, reduced opioid use, improved knee joint mobility, and an increase in patient tolerance for physical therapy and rehabilitation. The techniques for ketamine administration and dosing varied significantly, which may explain the inconsistencies between the reports. In addition, some of the studies, even those of high quality, used nitrous oxide in both the study and control groups. Nitrous oxide has NMDA receptor antagonist properties, as does ketamine. None of the studies reported whether patients were taking methadone, dextromethorphan, memantine, or magnesium sulfate, which are NMDA receptor antagonists too. The concomitant use of NMDA receptor antagonists, other than ketamine, may have interfered with the realization of analgesic effects of ketamine. Although it is largely accepted that NMDA receptor antagonism at the spinal level explains most of the analgesic effects of ketamine, it also interacts at other multiple receptors centrally, including, cholinergic receptors, nicotinic and muscarinic, adrenergic, central NMDA, and non-NMDA glutamate receptors. These influences may potentially explain why patients treated with other NMDA receptor antagonists had improved with ketamine as well. Ketamine also interacts with opioid receptors at supraspinal sites, where it produces supraspinal antinociception. Some of the studies did not report whether the participants were opioid naïve or opioid dependent. That might be an important determinant of the analgesic effect because opioid dependent patients are shown to benefit from the ketamine significantly. None of the examined randomized controlled trials assessed the effects of ketamine on opioid dependent patients. The variability between the outcomes of ketamine utilization for perioperative analgesia for knee surgeries might be, at least partially, explained by these findings.