John L Gibbons, BS
Sidney Kimmel Medical College at Thomas Jefferson University
SUMMARY POINTS
Ketamine is an NMDA receptor antagonist derived from phencyclidine that causes a dissociative anesthetic state.
Ketamine has a strong, immediate effect making it valuable in painful orthopedic procedures.
Ketamine has been shown to decrease opiate consumption 24 hours postoperatively across a variety of orthopedic procedures.
There is moderate evidence suggesting ketamine reduces the incidence of chronic postsurgical pain.
There is increasing attention on ketamine as a tool to mitigate the opioid crisis.
ANALYSIS
Background
Ketamine, a commonly used intravenous anesthetic, plays a significant role in preoperative and postoperative care (1). Derived from phencyclidine, it acts as a noncompetitive antagonist of NMDA receptors, inducing anesthesia within the central nervous system. Moreover, ketamine exhibits pronounced sympathomimetic effects, making it suitable for patients with hemodynamic instability or those susceptible to respiratory depression (1-2). Its dissociative anesthetic state offers immediate pain relief and amnesia, leading to its widespread application in orthopedic procedures such as trauma management, fracture reductions, amputations, total knee replacements, and spine surgeries (3).
In response to the ongoing opioid epidemic, ketamine has garnered attention as a potential tool to mitigate opioid consumption and reduce the occurrence of chronic pain (4). Given that orthopedic surgery ranks among the highest specialties in terms of opioid prescriptions, it is essential for orthopedists to possess knowledge about the effects of ketamine, its appropriate usage, and its role in addressing the opioid crisis (5).
Analysis
Ketamine was initially introduced to clinical practice as a novel anesthetic able to provide a wide range of effects including amnesia, analgesia, loss of consciousness, and immobility. Its popularity eventually diminished due to the extreme adverse effects: problems with attention, learning, memory, dreamlike states, and hallucinations (1-2). More recently, ketamine has returned as an additional tool to regional and local anesthesia. A systematic review and meta-analysis of 20 different orthopedic studies comparing ketamine to a placebo found ketamine to be an effective adjuvant in pain management. At low doses (0.1 - 0.5 mg/kg), it was shown to provide analgesia and opioid-sparing effects in the first 24 hours after painful orthopedic procedures including total joint replacement, spine surgery, arthroscopy, and trauma (6). Moreover, the low-dosage has not demonstrated the extreme adverse effects commonly associated with ketamine, specifically hallucinations (7).
While ketamine has shown to be an alternative analgesic in painful orthopedic surgeries, one of the most promising potential benefits is its role in mitigating the opioid crisis. Since ketamine does not act on opioid receptors, it does not carry the same risks as opioids. This idea has been explored as a means to limit opioid consumption post-operatively. One study conducted a meta-analysis on the efficacy of ketamine in adolescent idiopathic scoliosis patients undergoing spinal fusion. The systematic review included five randomized clinical trials and found that intraoperative and postoperative continuous low dose ketamine infusion significantly reduced postoperative opioid consumption (8).
In a randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy of ketamine on opioid pain-controlled analgesia (PCA), the most effective dose for reducing postoperative opioid consumption, while limiting the occurrence of adverse events, was 0.75 mg/ml. The study participants consisted of 107 patients receiving major lumbar spinal fusion surgery. Each participant was randomly placed in a group receiving varying doses of adjunct ketamine with oxycodone PCA for 24 hours postoperatively (0.75 mg/ml, 0.5 mg/ml, 0.25 mg/ml and placebo). At the end of the 24 hours, the total oxycodone PCA was measured and compared across each group. Compared to 0.5 mg/ml, 0.25 mg/ml and control, the 0.75 mg/ml dose group required 25% less oxycodone 24 hours postoperatively (Figure 1). While the study’s primary outcome was cumulative oxycodone PCA 24 hours postoperatively, the 0.75 mg/ml dose also showed reductions in oxycodone PCA consumption at 48 hours and 72 hours postoperatively (9).
Figure 1. Postoperative cumulative oxycodone (top row) and S-ketamine (bottom row) consumption during the first 24 h in four patient-controlled analgesia (PCA) treatment groups (G1-G4). PCA, patient-controlled analgesia. Box plots show the median and 25–75th percentiles, and the whiskers indicate the minimum and maximum. Blue diamonds show the mean oxycodone consumption in each plot. SEE ARTICLE from Brinck ECV, Virtanen T, Mäkelä S, Soini V, Hynninen VV, Mulo J, Savolainen U, Rantakokko J, Maisniemi K, Liukas A, Olkkola KT, Kontinen V, Tarkkila P, Peltoniemi M, Saari TI. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021 Jun 7;16(6):e0252626. doi: 10.1371/journal.pone.0252626. PMID: 34097713; PMCID: PMC8183989.
The American Society of Regional Anesthesia and Pain Medicine have released recommendations and guidelines for the use of ketamine for acute and chronic pain. Subanesthetic intravenous ketamine should be considered for orthopedic procedures associated with severe postoperative pain, namely spine, trauma and limb surgeries. However, procedures with low expected pain, like soft tissue hand procedures, do not benefit from ketamine infusions and are properly managed by acetaminophen and NSAIDs (3,10-11). For opioid-dependent patients undergoing surgery, ketamine should be considered as an adjunct therapy to limit postoperative use of opioids. However, there is not substantial evidence supporting ketamine as a sole analgesic agent for patient controlled analgesia meaning another analgesic is required to reduce pain. It is also worth noting that ketamine has not had the same success in mitigating chronic pain. Ketamine is moderately effective in treating chronic regional pain syndrome; however, it has not been shown to provide pain relief to chronic pain conditions secondary to neuropathic pain, fibromyalgia, cancer pain, ischemic pain, migraine headache, and low-back pain (3).
Another potential direction where ketamine can reduce chronic opioid use is in treating chronic postsurgical pain. Post-surgical pain is a common pathway for patients to become opioid dependent due to overprescribing of opioids without a clear plan for tapering (12). In a meta-analysis exploring ketamine's impact on chronic postsurgical pain (CPSP), it was inferred that ketamine might lower the occurrence of CPSP. This analysis encompassed 20 randomized controlled trials and presented certain evidence of ketamine's effectiveness in reducing CPSP. However, the study acknowledged inconsistent assessment tools and follow-up, leading to limitations in the findings (13). Opioid prescribing practices have become strict, but the incidence of postsurgical pain still remains high (12). Substantial further research is imperative to ascertain ketamine's efficacy in alleviating another risk factor for chronic opioid use.
Discussion
Ketamine has established its worth as a valuable asset in postoperative pain management and in addressing the opioid crisis. It has been shown to decrease postoperative opioid consumption across a diverse patient population with minimal serious adverse effects. As orthopedic surgeons grapple with the repercussions of the opioid crisis, it becomes increasingly crucial for medical professionals to recognize and comprehend the utility of ketamine in orthopedic procedures. While certain questions regarding ketamine's application for various types of pain remain unanswered, future research into ketamine's potential to alleviate chronic pain originating from surgery could significantly contribute to addressing another prevalent complication in orthopedic surgery and the opioid crisis.
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Brinck ECV, Virtanen T, Mäkelä S, Soini V, Hynninen VV, Mulo J, Savolainen U, Rantakokko J, Maisniemi K, Liukas A, Olkkola KT, Kontinen V, Tarkkila P, Peltoniemi M, Saari TI. S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: A randomized, double-blind, placebo-controlled clinical trial. PLoS One. 2021 Jun 7;16(6):e0252626. doi: 10.1371/journal.pone.0252626. PMID: 34097713; PMCID: PMC8183989.
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