Intraoperative Ketamine for the Opioid-Naïve Patients: Move Along Folks, Nothing to See Here?

The use of ketamine for acute and chronic pain has skyrocketed in recent years. This is driven by a multitude of factors, including the search for nonopioid alternatives and recognition of the role that N-methyl-d-aspartate (NMDA) receptors play in the “chronification” of acute pain.1 Ketamine, an NMDA receptor antagonist, is associated with powerful analgesic effects, amnesia, and (in high doses) loss of consciousness.2 It is used to treat depression,3 and it can have a positive impact on the affective-motivational component of pain. Among the various causes of chronic pain, persistent postsurgical pain has generated enormous interest in the surgical, anesthesia, and pain management communities in view of the growing rates of surgery and because it is a prime target for prevention. In 1 large study that enrolled over 20,000 surgical patients in a European registry, the rate of persistent postsurgical pain was found to be 11.8%.4 For tissue trauma related to elective surgery, preemptive interventions can be undertaken, including pharmacological-based treatment, addressing psychological risk factors, and modifying the surgical and anesthetic technique. Chronic back pain is one of the most controversial indications for surgery, with some studies finding that >40% of individuals will continue to experience persistent pain postoperatively.5 This has led to multiple studies evaluating various preventive strategies to reduce the risk of persistent postsurgical pain after spine surgery, and many studies have evaluated ketamine for decreasing acute postoperative pain in this context.6 For all types of surgeries, with incidence of persistent postoperative pain ranging from 0% to 80% depending on the type off surgery, the data collectively support a small preemptive effect for ketamine. A systematic review found that 12 people need to be treated to save 1 person from persistent postsurgical pain at 3 months and that 14 people need to be treated to save 1 person from persistent postsurgical pain at 6 months.7 This indicates that ketamine is efficacious in preventing postsurgical pain in 7%–8% of the patients undergoing surgery, with the probability of success declining with time. Ketamine provides an attractive nonopioid alternative for providing analgesia in the perioperative setting, along with the tantalizing possibility of improvement in long-term analgesic outcomes. Ketamine is a racemic mixture of 2 enantiomers, stereochemical configurations of enantiomers (S(+) and R(−)), with S-ketamine being twice as potent as the racemic mixture.8 Administration of ketamine or S-ketamine to opioid-tolerant patients with chronic pain who undergo spine surgery has been shown to reduce pain and opioid requirements for up to 6 weeks9 and 1 year10 after spine surgery. However, it is unclear whether these findings are applicable to opioid-naïve individuals who undergo spine surgery. In this issue of Anesthesia & Analgesia, Brinck et al11 report findings from their study on the use of intravenous S-ketamine during the intraoperative period in 198 opioid-naïve patients who had lumbar spine fusion surgery. Participants were randomized to 1 of the 3 groups to receive, until the end of the surgery, 0.9% sodium chloride in the control group or S-ketamine in the other 2 groups. The S-ketamine groups were subdivided into “low”- and “high”-dose groups. Participants in both groups received a preincisional bolus of ketamine of 0.5 mg·kg−1 followed by an intraoperative infusion of 0.12 mg·kg−1·hour−1 (low dose) or 0.6 mg·kg−1·hour−1 (high dose). The authors reported no significant difference among the 3 groups for the primary outcome of the study—cumulative opioid (reported by authors as milligram of intravenous oxycodone) consumption in the first 2 days after surgery—or in the intensity of pain at 3 months and 2 years after the surgery. This study’s methodology should be appreciated for including a placebo control group, blinding of participants and data collectors, comparison of 2 different doses of S-ketamine, measurement of the severity of depression using a validated instrument, Beck Depression Inventory-II (BDI-II), and long-term follow-up. However, there are some critical limitations, including the relatively low dose of ketamine (even in the high-dose group) as compared to doses used for treating chronic pain,3,12 concerns about the ability to detect a small effect size (eg, 80% power to prevent an outcome such as persistent pain that has a low incidence), and failure to perform an intention-to-treat analysis. The high number needed-to-treat (prevent) persistent postoperative pain calculated from the meta-analysis performed by McNicol et al7 also suggests that Brinck et al11 should have considered predictive modeling to determine subgroups of patients that may have benefitted from preventive ketamine. In other words, despite the number of participants being higher than most studies on preemptive analgesia, the study by Brinck et al11 was probably still underpowered given that not everyone who undergoes surgery will experience persistent pain afterward. The study by Brinck et al11 represents an important contribution to the literature on ketamine and persistent postoperative pain even though it raises more questions than it provides answers. For example, did the authors fail to give the medication to the right patients at the right dose for the right amount of time, or does S-ketamine truly lack efficacy in relieving postoperative spine pain? The absence of a dose–response effect for S-ketamine, as evidenced by similar outcomes of the participants in the 2 groups that received doses of S-ketamine that differed 5-fold, is an interesting finding. There is evidence of dose-responsiveness for the longevity of analgesic benefit with ketamine, although if both doses were subtherapeutic (which might have been the case here), a dose–response relationship would not be appreciated.3 Extrapolating the observations regarding the potential of epidural analgesia to prevent phantom limb and post-thoracotomy pain, one might infer that the longer in advance of surgery the intervention is started, the more likely a preemptive effect will be realized.13 Perhaps starting the infusion the day before or even on the morning of surgery and continuing it until discharge, to minimize peripheral and central sensitization, might have yielded positive results. Another question that this study raises is whether ketamine acts differently in patients who are on opioids10 versus those who are opioid-naïve, with efficacy in the former but not the latter group. This is pertinent because the recent guidelines for use of ketamine in the acute pain setting found grade B evidence to support perioperative ketamine as an opioid-sparing adjuvant.14 Activation of the NMDA receptor plays a fundamental role in opioid-induced hyperalgesia.1 Ketamine is a noncompetitive antagonist of this receptor. Ketamine decreases the “wind-up” phenomenon, and the antagonism is more effective if the NMDA receptor has been previously “activated” by glutamate binding, a phenomenon referred to as “use dependence.” Activation of NMDA receptors resulting in hyperalgesia is often observed with chronic use of opioids or with administration of intravenous remifentanil infusions in relatively high doses in the perioperative period.15 This opioid-induced hyperalgesia can lead to high levels of pain in the perioperative period that can be challenging to treat. Ketamine is often administered in this setting to mitigate this effect and to improve analgesia. The lack of efficacy of S-ketamine in opioid-naïve patients in the study by Brinck et al11 may also be due to the lack of preexisting activation (or hyperactivation) of NMDA receptors. Inadequate dosing may also have played a role, although one should be cognizant of the fact that the infusion rate of S-ketamine in the higher-dose group was considered to be equianalgesic to a racemic ketamine dose of 1.2 mg·kg−1·hour−1. However, there are few clinical trials to support this pharmacokinetic study equivalency ratios, and the results of animal studies are mixed regarding whether S-ketamine is more potent or efficacious than racemic ketamine. Other factors to consider are the type of surgery and the character of pain (neuropathic versus nonneuropathic). The low-dose ketamine group contained a lower percentage of individuals with baseline neuropathic pain than the control group. Whereas a recent meta-analysis found no differences in outcomes with ketamine between different pain categories (neuropathic versus nonneuropathic versus nociplastic),12 the number of participants in these studies was very small, and the evidence for neuropathic pain is more robust than for nonneuropathic pain. The surgical setting used by Brinck et al11 (spine surgery) has been examined in other studies on perioperative ketamine infusion, with analgesic benefit demonstrated in participants receiving ketamine.10 Hence, it is difficult to make the argument that administration of ketamine to opioid-naïve patients undergoing nonspine surgery would yield results different from those reported by Brinck et al.11 Brinck et al11 found no impact of ketamine on the severity of depression in participants in the S-ketamine groups in this study. Ketamine has been shown to be an effective antidepressant when administered in a dose of 0.5 mg·kg−1, although the effect may be limited to a few weeks.3 An inadequate dose of S-ketamine is unlikely to be the cause of this observation, because bolus doses of S-ketamine administered in the study by Brinck et al11 were twice as high as those recommended for treatment for depression.2 The lack of observed antidepressant effects of S-ketamine may be due to other reasons, including the possibility of a type II error, absence of severe depression in participants in this study as indicated by the low BDI-II scores, or because ketamine was administered to anesthetized patients. Other issues to consider here are whether ketamine might be effective only for individuals who have clinical depression. This is an important aspect to consider, because depression is an independent risk factor for persistent postsurgical pain. Ketamine is known to have a greater impact on the affective-motivational component of pain as compared to the sensory-discriminative component, although this effect may be short-lived.16 However, ketamine has been administered through intravenous3 and intranasal17 routes to alleviate depression. Treatment with ketamine is associated with attenuation of suicidal ideation, an effect that can last for up to 3 days following a single administration.18 Furthermore, intranasal esketamine (an enantiomer of ketamine) appears to have an ultrarapid antidepressant effect for major depressive disorder with efficacy for up to a month.17 Perhaps the most enduring legacy of the study by Brinck et al11 will be the new lines of enquiry that emerge through the lack of definitive results. The advent of new analgesic medications typically follows a predictable course guided by regulatory processes characterized by industry-sponsored, methodologically robust studies for patent-protected products, while the study of already-approved medications for off-label analgesic purposes tends to be more haphazard with small, methodologically flawed studies being the norm for drugs such as ketamine that are not protected by patents. The ambitious studies that need to be conducted in light of the findings by Brinck et al,11 and that we are proposing, would require enormous resources. They would entail enrolling adequate numbers of patients to account for the unpredictable nature of persistent postsurgical pain, variations in surgical technique, a diverse patient population, and subgroup analyses planned a priori; they would utilize different treatment paradigms to include the dosing and timing of administration; objective evaluation of the preventive effects of ketamine for a variety of different surgeries that involved acute versus chronic pain and neuropathic versus nonneuropathic pain; and they might explore the role of ketamine as part of a multimodal analgesic regimen that not only included other medications but possibly also nerve blocks, psychological therapies, and integrative medicine. Until these resources are allocated, these questions will continue to plague our profession. Clearly, the issues at stake, which include long-term disability and opioid misuse, are worth the costs of answering the questions. DISCLOSURES Name: Anuj Bhatia, MBBS, MD, FRCA, FRCPC (Anesthesia & Pain Medicine), FFPMRCA. Contribution: This author helped write the manuscript. Name: Vwaire Orhurhu, MD, MPH. Contribution: This author helped write the manuscript. Name: Steven P. Cohen, MD. Contribution: This author helped write the manuscript. This manuscript was handled by: Honorio T. Benzon, MD.

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