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Postoperative Ketamine: Time for a Paradigm Shift

Sobey, Christopher M. MD; King, Adam B. MD; McEvoy, Matthew D. MD

Regional Anesthesia and Pain Medicine: July/August 2016 - Volume 41 - Issue 4 - p 424–426
doi: 10.1097/AAP.0000000000000429

*Division of Pain Medicine, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN; †Division of Critical Care Medicine, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN; and ‡Division of Multi-specialty Anesthesiology, Department of Anesthesiology, Vanderbilt University School of Medicine.

Accepted for publication April 23, 2016.

Address correspondence to: Matthew D. McEvoy, MD, Division of Multi-specialty Anesthesiology, Department of Anesthesiology, Vanderbilt University School of Medicine (e-mail:

The authors declare no conflict of interest.

Thomas Kuhn (1922–1996) is influential in academia for authoring, in 1962, The Structure of Scientific Revolutions. In it, he argues that science does not progress as a linear accumulation of new knowledge; rather, disciplines undergo periodic revolutions called “paradigm shifts.”1 A scientific paradigm is a specific theoretical orientation that is built upon a particular epistemology and research methodology and demonstrates the beliefs of a particular scientific community at a particular time in history. As such, paradigms not only provide a framework but also guide the types of questions that will be asked, providing the theoretical basis from which any results are evaluated. According to Kuhn, a scientific paradigm goes through 3 distinct phases. The first is a “prescience” phase defined by a period that lacks a reigning paradigm, but from which the archetype begins to emerge. The second is a “normal science” phase, when research is undertaken to prove and expand the central paradigm by problem solving to approach the “real answer.” During this phase, results are evaluated in terms of the paradigm boundaries, and results that do not conform to the paradigm are seen not as refuting the paradigm but as the mistake of the researcher. The final stage, the “crisis” phase, is the point at which enough evidence has been mounted to challenge the reigning paradigm—and at which a new paradigm could emerge to become accepted by the community. Modern health care is at such a point, particularly in the perioperative period, with its understanding of managing analgesia. Opioids, having been used for over a century as the primary means of providing perioperative analgesia, are now being seen as creating significant problems at the individual and societal level.2 However, a new paradigm for managing and researching perioperative pain is emerging and is yet to be defined.

Despite the mounting evidence against the routine use of opioids, they remain the primary pharmacotherapy for perioperative analgesia. With the expanding literature of the dangers of opioid use, the growing societal consequences of tolerance, abuse, misuse, addiction, and the development of opioid-induced hyperalgesia and chronic postsurgical pain, there is renewed interest in using nonopioid analgesics in the perioperative period.3,4 In this issue of Regional Anesthesia and Pain Medicine, Schwenk et al5 describe the use of perioperative ketamine. Recent studies have demonstrated the inherent risks of postoperative opioid use contributing to danger in the immediate postoperative period, as well as the rising epidemic of abuse.2,6 An estimated 4% to 20% of all opioid prescription pills are used nonmedically, accounting for half a billion doses per year of misused opioid prescriptions. In addition, it is reported that 4 of 5 heroin users reported that their opioid use began with prescription pain medication.7 From 1999 to 2014, more than 165,000 deaths have been attributed to opioid pain medications, and the death rate from opioid abuse continues to climb.2

In light of this epidemic, practitioners are consistently examining the proper applications of nonopioid analgesics, including ketamine, as alternative therapies to opioids.8 Ketamine has been used for acute and postoperative analgesia for over 5 decades.9 Its ability to produce a dissociative anesthetic state with significant analgesia provides benefits such as sedation with an acceptable operating environment, use as a supplemental analgesic that can dramatically reduce opioid requirement, and the ability to reduce opioid-induced hyperalgesia and tolerance.10,11 More recently, its use as a low-dose perioperative infusion has demonstrated continued opioid-sparing qualities in the postoperative period based on its primary mechanism of N-methyl-D-aspartate receptor antagonism.12 Studies promoting the perioperative use of ketamine in attenuating postsurgical pain are present, yet the significant variations in timing and dosing have prevented a unified approach to administration.13

One of the factors liming the increased acceptance of ketamine use as an analgesic relates to the concern for development of adverse drug effects (ADEs). The literature surrounding these ADEs is copious. Ketamine-related ADEs are thought to include psychocognitive effects such as hallucinations, cardiovascular effects from inhibition of catecholamine reuptake, neurologic effects such as tonic-clonic movements, and increased intracranial pressure, and the potential for gastrointestinal and respiratory events.14 The classic teaching is that the presence of these ADEs is ubiquitous with ketamine use, rather than being dose dependent.15 This misconception needs to be rectified. Furthermore, some of the traditional dogma has been clearly disproven, such as the increase in intracranial pressure.16 Another major roadblock to the postoperative use of ketamine is the classification of ketamine as an anesthetic compared with an analgesic. Ketamine has the unique ability to provide both potent analgesia and anesthesia. To date, it is most commonly classified as an anesthetic agent based on these dissociative qualities, and thus its use is often restricted to areas where anesthetic services are either offered or readily available based on hospital policies or state nursing regulations. Obviously, there are pros and cons of these policies, by ensuring safe delivery of medications that could result in an anesthetized state; however, these restrictions do constrain the analgesic options offered in the hospital setting.

In this issue of the Regional Anesthesia and Pain Medicine, Schwenk et al provide a large retrospective, observational study that describes the routine use of perioperative ketamine infusions at their institution with 3 defined goals: (1) identifying patients most likely to receive a ketamine infusion, (2) identifying the spine procedures associated with initiating the infusion, and (3) determining the prevalence of ADEs associated with ketamine infusions as well as the frequency of discontinuation following these drug effects.5 As admitted by the authors, the study is limited in its ability to make generalizations about the benefits of ketamine utilization, such as decreased opioid use, speed of recovery, and improvement of analgesia compared with conventional options, due to the retrospective methodology. However, a primary benefit of this article is in dispelling the pervasive myth that intolerable or significant ADEs always occur with the use of this analgesic. The vast majority of the patients receiving the infusions tolerated them well, and the vast majority of those who experienced adverse effects demonstrated resolution of the unwanted symptoms by discontinuing the infusion. Furthermore, the study demonstrates that doses of less than 5 μg/kg per minute produce few, if any, ADEs. In addition, clinically relevant analgesia was produced at doses of 2 μg/kg per minute. Clarifying this misconception can serve to promote further study of ketamine as a reasonable postoperative analgesic option by breaking down the barriers of use.

The key to mitigating the risks and benefits associated with perioperative nonopioid analgesics lies within determining the dose of these medications that provide adequate pain management, while minimizing the ADEs. In that vein, it has been shown that low-dose ketamine infusions can produce notable analgesia without significant adverse effects, providing a useful tool that continues to be underused.17 In regard to the lack of ubiquitous acceptance of ketamine in the perioperative period, there is frequently pushback involving multiple components of the postoperative care team, including the hospitals, nursing staff, and pharmacy and therapeutics committees. This is despite evidence that low-dose analgesic infusions can be administered safely and effectively with minimal adverse effects.

As recent evidence shows that massive reductions in perioperative opioid use are not only possible but also associated with improved outcomes,18 it is time for our specialty to lead the way in promoting a safe pathway for low or no-opioid perioperative analgesia. The evidence espousing the dangers of the status quo use of opioids as a primary analgesic in the postoperative period continues to mount. Despite the significantly higher morbidity and mortality of opioid administration, they remain the most “comfortable” choice of providers. In fact, while the medical literature is littered with peer-reviewed publications warning of the dangers of opioid use,6 a search for mortality related to ketamine use produces no significant results. In contrast to opioids, the use of intravenous ketamine for acute pain provides the option of effective analgesia without significant adverse effects. As such, we commend Schwenk et al on not only their recent report but also their widespread use of a safer analgesic option. The future of routine perioperative pain management should take note of their findings as one piece in the puzzle and add this to the construction of plans that result in adequate analgesia and reduced ADEs while promoting quicker postoperative functional recovery, a concept that we call optimal analgesia. However, as increased opioid prescribing has led to a direct rise in opioid abuse, there is understandable concern about the misuse of ketamine as a recreational drug.19 The exact incidence of ketamine abuse is currently unknown, but the possibility for abuse points to the need for using multiple agents for pain control, minimizing exposure and adverse effects from each one.20 Limiting ketamine use to the inpatient setting should limit both the accessibility to the medication for those at risk, as well as the potential for abuse and misuse.

We can no longer turn a blind eye to the dangers of routine postoperative opioid use. We should demand that policies are put in place whereby all appropriate and safe treatment options are available throughout the perioperative period. Furthermore, we should lead the way in creating an expectation that care teams ensure the maximum use of nonopioid agents prior to using opioids for managing postoperative pain. Rather than be shackled to opioids by conventional dogma, we should embrace current evidence-based options for the betterment of our patients. This represents a paradigm shift, no less than an analgesic revolution, and it is long overdue.

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Copyright © 2016 by American Society of Regional Anesthesia and Pain Medicine.