Efficacy and Value in the Treatment of Chronic Pain: A Rational for Inpatient Program and Nursing Process Development

Use of Low Dose Intravenous Ketamine:

Efficacy and Value in the Treatment of Chronic Pain:

A Rational for Inpatient Program and Nursing Process Development

Joan Riswold

Western Governors University

College of Health Professionals

February 15, 2018

C823 Task 2

Use of Low Dose Intravenous Ketamine: Efficacy and Value in the Treatment of Chronic Pain: A Rationale for Inpatient Program and Nursing Process Development

Chapter I
A1.Background
Chronic pain is a national epidemic (IOM, 2012: Breivik, et al., 2013; Kennedy, et al., 2014, 979). In the medical treatment of chronic pain, typically the methodology employed is one of trial and error. Many of these unfortunate patients have suffered for years and have undergone multiple diagnostic and treatment modalities; including opioids, anti-inflammatories, muscle relaxants, anti-seizure medications, nerve blocks, spinal and peripheral nerve stimulations, trigger point injections, epidural injections, physical therapy, psychotherapy and medical management (Patil & Anitescu, 2012, pp. 263-269). Unfortunately, even with the deployment of all these modalities, only 30-40% percent of patients report adequate or sustained pain relief. When used in sub anesthetic dosages also known as “low dose” ketamine, it has demonstrated efficacy in achieving pain control when other medications do not. This is largely believed to be due ketamine’s unique properties and mechanism of action (Niester, et al., 2013).
Johannes et al., in 2012 attempted to quantify the prevalence of chronic pain in the United States (p. 1230). They distributed surveys to 35, 718 Americans ages 18 and older. This survey was designed as a population-based cross-sectional representative sampling of the American population. The criteria for inclusion required the respondents to have recurrent pain, and pain that has lasted greater than six months. There were 27,035 survey respondents, and of that, 30.7% percent or 10, 040 people who met inclusion criteria. Within this group, 89% percent reported experiencing pain for a year or more, and 86% percent reported having pain more than two to three times per week. They concluded that the prevalence of chronic pain affects one third of all Americans. And, as previously mentioned only 30% percent to 40% of those diagnosed with chronic pain, obtained relief with conventional therapies.
In another study conducted by Kennedy, et al., in 2014 the authors cited the incidence of chronic pain at 19% percent, or 39 million Americans (p. 983). These patients reported frequent and persistent pain: of those millions patients, 67% percent reported their pain constantly present and of that, 50.5% described their pain as excruciating and unbearable (Gaskin & Richard, 2012, p. 715; Kennedy, et al., 2014, 983).
Though there is significant disparity in the prevalence data presented here, it serves to illustrate the complexity of identifying a concise definition of chronic pain, the methodology used to quantify its prevalence, and the criteria for study participant inclusion. Despite these challenges, it is evident that chronic pain is a serious health problem in the United States. Typically refractory to traditional pain management modalities, many of people experience long-term pain for years. This is the overarching framework for the discussion in this submission and the rationale for the use of ketamine.
In addition to the human suffering and large numbers of people struggling with chronic pain, the total costs associated with this condition are staggering. These costs include, medical treatment, time lost from work, and lower worker productivity, and is estimated to be between $560 and $635 billion dollars annually. Put into perspective, just the associated medical treatment costs, are between $261 and $300 billion annually. This is equivalent or greater than monies spent on treatments related to cancer ($243 billion), diabetes (188 billion), and heart disease ($309 billion) (Gaskin & Richard, 2012, p. 715). It is important to note that chronic pain is also one of the major reasons why patients seek medical treatment. As medical providers, it is necessary that we identify the most cost effective and efficacious treatment. The magnitude of this problem cannot be overstated.
The passage of the Patient Protection and Affordable Care Act of 2010 requires the Department of Health and Institute of Medicine to examine the current state of chronic pain, and as such has determined it to be national health issue. The National Center for Health Statistics and the Agency for Healthcare Research and Quality (AHRQ), along with other state and federal agencies have been tasked to obtain national data on pain prevalence, incidence, and treatments (IOM, 2012, p.55). In a 2011 report brief, the IOM has concluded that currently pain prevention, assessment, and treatment options are inadequate (IOM, 2012, p. 64).
The above figures do not include patients whose chief complaint is acute pain; and it is important to distinguish between these two symptomologies. Specific characteristics of acute pain are: the origin is from an inciting event, it has a sudden onset, and time in pain is limited. Though there is no universally accepted definition od chronic pain, to differentiate it from acute pain, the following characteristics are present; there is no time limit and it can last for three months to years, it produces pathophysiologic organ-system changes, it serves no useful purpose, and typically its origins are found in acute pain. But because of prolonged neuronal stimulation, structural changes occur in the central nervous system (Tighe, et al., 2015, p. 1807). This creates what is known as” central sensitization”, which is caused by maladaptive changes to perception within the central nervous system (Leung, et al., 2016, p. 3). It has been hypothesized that this may be caused by prolonged use of opioids (Tighe, et al., 2015, p. 1809)
Typically, when surgery or an injury occurs there is an associated recovery period. Normally as healing progresses, pain will/should diminish. However, in some patients the pain lingers substantially longer and extends beyond the anticipated healing period. In addition, the pain response is disproportionately greater than the observable injury (Leung, et al., 2016, p. 5). Within the condition of chronic pain a subset has been identified and is referred to as refractory chronic neuropathic pain. This condition creates state of hyperalgesia, which causes increased sensitivity to virtually any stimuli to the area injured. Examples of conditions, which may lead to chronic neuropathic pain, include, phantom limb pain, post-herpetic neuralgia, chronic regional pain syndromes, diabetic neuropathy, and pain following spinal cord injury (Blue Advantage, 2015).
It is necessary to understand the evolution of chronic pain to better appreciate how certain medications may hold promise for some patients within this population. One such medication is ketamine.
Chronic pain is a phenomenon characterized by the development of a centralized locus within the central nervous system (CNS), called “central sensitization”. This is formed when there is an abnormal enhancement and amplified excitability of CNS neurons. This occurs secondary to changes in neural membranes / ion exchange channels, neurotransmitter uptake, and increased activation of inhibitory mechanisms and amplified synaptic efficiencies (Leung, et al., 2016, p. 5). N-methyl-D-aspartate (NMDA) is an excitatory inotropic glutamate receptor present in the brain. Prolonged activation or “wind up “of the NMDA receptors by the excitatory neurotransmitter glutamate results in plastic changes in the spinal cord and brain with the upregulation of glutamate at the NMDA receptor resulting in central sensitization, (Patil, et al., 2012, p. 263). As a result, pain perception is no longer connected to the intensity of the peripheral stimuli, but can be elicited even in the absence of noxious stimuli. For example, air movement over an extremity or a gentle touch can elicit excruciating pain. Though not fully understood, ketamine acts by blocking the uptake of glutamate at the NMDA receptor and can effectively reduce or minimize the development of central sensitization (Leung, et al., 2016, p. 7: Patil & Anitescu, 2012, p. 263). Opioids have no affinity at the NMDA receptor site and though some pain relief maybe experienced it is non-specific to NMDA receptors, which is believed to be the culprit in the creation of chronic pain (Peltoniemi, et al., 2016, p. 1059).
Ketamine is a well-established schedule III controlled substance and FDA approved anesthetic. It was first introduced in 1964 and at that time is use was mostly in veterinary practice. However, because of its safety profile it was found to be ideal for treating the injured during the Vietnam War and it continues today to be the drug of choice when attending those on the battlefield. However, because of its safety profile, the general public has the abused this drug as a hallucinogen. Today, it continues to be used as an anesthetic in veterinary medicine and within the past decade has gained popularity as an analgesic in emergency room medicine, operating room theaters, postoperative pain management, chronic pain management and most recently, in the treatment of intractable depression. (Baldwin, et al., 2017). The latter is significant. It is easy to extrapolate that people who suffer from chronic pain often develop depression. Indeed, in an editorial by Baldwin, et al., (2017), published in Military Medicine, chronic pain and depression are comorbidities. These authors proffer that issues that exist with opioid medications, substance abuse, and fear of overdosing complicate chronic pain treatment. When added to a state of depression, it becomes more complicated. These authors proffer that ketamine has been identified as an effective treatment for both chronic pain and the symptoms associated with mood disorders including suicidality. The use of ketamine in the treatment of depression is beyond the scope of this submission, however this highlights the importance and necessity for including ketamine in chronic pain management.
Ketamine’s onset of action is within 30 seconds, and its redistribution half-life is between 7 and 15 minutes with an elimination half-life between two and three hours (Niesters, et al., 2014, p. 357). It is interesting, that despite drug’s half-life, ketamine has demonstrated prolonged periods of pain relief (sometimes weeks or months) even after it has been completely eliminated from the body. This is important when treating chronic pain, as prolonged relief is a chief goal in the treatment regimen, and with an additional benefit of reducing dependency on opioids.
Ketamine is classified as a dissociative anesthetic that produces profound analgesia and amnesia. For the purposes of this submission we will explore the current scientific literature for its sub anesthetic (low dose) infusions in the treatment of chronic pain refractory to conventional modalities. This will assist in the development and implementation of a nursing procedure and process for that purpose.
A2. Problem Statement
There is no silver bullet in the management of patients suffering from chronic pain. We have a population of patients within our community, who despite our best efforts in managing their pain, currently do not have access to all treatment modalities. As mentioned previously it is a multi modal application of treatments with a large variance in efficacy. For this population, it is not enough to just provide analgesia during a treatment, but equally important is the ability to provide sustained relief. Ketamine not only can safely provide significant analgesia, but in certain cases it can provide weeks or months of pain relief, however, to date the clinical trials remain inconsistent relative to ketamine’s efficacy in the long-term management of chronic pain. However, this should not preclude its use in acute exacerbations.
The study institution, a large Healthcare System in Southern California, (HSSC) is developing a multi-disciplinary innovative approach to pain management. Given the emphasis on the, Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores mandated by CMS, hospitals are focused on maximizing their scores. The HCAHPS scores have created a means to quantify a patient’s overall experience, including the quality, safety and efficiency of the care provided by institutions and stipulates a means for determining reimbursement. Equally important, if not more so, is the drive by CMS to incentivize providers to adopt appropriate and evidenced based medical care across similar communities and regions.
According to the most recent HCAHPS scores, pain control at HSSC is rated at 69% percent as compared to the national average of 71% percent. Once identified, both clinical and administrative leadership at HSSC realized a lost opportunity found in the decision to add ketamine to the IPS armamentarium (CMS, n. d.).
With the introduction of this a new treatment regimen at HSSC it is incumbent upon clinical leadership to identify the standard of care, best practices, and to conduct a critical evaluation of the current science and clinical applications. Based upon an extensive literature search a decision has been made by the inpatient pain service to include the administration of low dose ketamine infusions for patients admitted to the medical center with acute exacerbations of chronic pain. Heretofore this was not a treatment option for these patients at HSSC.
This submission will be considering the evidence to support its use, and the development of a comprehensive nursing process needed for the safe administration of ketamine at HSSC.
When HSSC first ventured into ketamine’s use for chronic pain, it was the emergency room physicians and nurses administering abbreviated doses of the drug on an outpatient basis in the emergency department (ED). HSSC’s ED is a Level I trauma center with an average daily census of 275 patients. Emergency room visits by patients who are categorized as “frequent flyers” (often drug seekers), is estimated to be between 3% percent and 8 % percent of total patient visits; but accounts for as much as 30% percent of billed charges. This in turn translates into significant time and substantial resources needed to provide a treatment in a suboptimal environment. Suboptimal because the staffing ratio in the ED is one nurse to four patients and according to the literature these infusions should be closely monitored and staffed as one to one. In addition the chaos and noise in the ED could result in a negative outcome for the patient. Chronic pain sufferers are the largest sub-group within the “frequent flyer” population (Olsen, et al., 2016). The rationale for providing our patients with this treatment modality is simple; we treat a significant number of patients with a myriad of chronic pain conditions and as such, should provide a treatment that has been determined by clinicians to be effective. Once the decision was made to provide this treatment on an inpatient basis, the ED discontinued the infusions.
As medical and nursing providers, it is important to realize we are professionally and morally responsible for providing relief to those that suffer. Many of these patients have been maligned or marginalized over the years as drug seekers and malingerers. For several decades, some conditions, specifically chronic regional pain syndrome (CRPS), and fibromyalgia were not even considered or accepted by the medical community as valid conditions. We owe it to our community and patients to provide a treatment modality that has shown success in the amelioration of chronic pain. Considerable evidence based science and best practices have been identified in the treatment of chronic pain with the use of ketamine. However, there is a significant caveat, that no universally accepted clinical guideline or protocol for the use of sub anesthetic ketamine infusions for chronic pain has been identified or endorsed (Maher, et al., 2017, p. 661: Jonkman, et al., 2017, p. 3). This is complicated by two factors. The first is that there is no universally accepted definition of chronic pain, and secondly there is no universally accepted definition of “low dose” ketamine. Consequently when reviewing the clinical trials there is significant variation in the applied methodology, sample size, criteria for patient inclusion, dosing and length of infusion times.
A3a. Practice Change and Quality Improvement
The decision to add ketamine infusions to the armamentarium of HSSC’s pain management program is both a practice change and quality improvement endeavor. Its off-label use as an analgesic for treating chronic pain has gained traction as an option that can ameliorate suffering, improve function and reduce opioid use (Allen, C., & Ivester, J., 2017, p. 373: Schidler, et al., 2013). It represents a change in practice, because it has never been offered as an inpatient treatment at HSSC. It represents a quality improvement in our ability better treat this population where other treatment modalities have failed, or have become ineffective over time. In addition, a review of studies and practices employed by researchers has provided inpatient pain management service (IPS) and the HSSC pharmacy with substantial information regarding the use of ketamine infusions for this population.
The scope of this project is relatively small however the number of departments involved is many, and the potential benefits for some patients will be significant. Once the decision is made to adopt ketamine infusions as a treatment modality HSSC, the identification of a physical location for administration is needed. In addition, an evaluation of the literature relative to medication safety, monitoring requirements, and staff skill is needed. The primary focus of this submission is to provide the rationale for the use of ketamine based upon the literature. This in turn will be the driver and rationale for the nursing process design and its components.
An initial assessment of the environment is needed to identify the current resources available and the projected needs. This will ensure an appropriate allocation of those resources, including the physical location for treatment, staffing requirements, equipment, training and education. This will safeguard that all procedural and process tasks are consistently followed by both physicians and nursing. As mentioned, this project will entail the participation and collaboration with several institutional departments; including the inpatient pain management team, anesthesia residents, pharmacy, nursing administration, clinical nursing leadership, education, quality management, and risk management.
With the introduction of a new nursing procedure and process it is important to understand the culture and administrative processes within the institution to ensure a successful implementation and acceptance of this new process by frontline staff. The development of a procedure, process, and implementation plan for the appropriate and safe administration of ketamine will be completed within an eight-week period.
A3b. Rationale
The rationale for developing this process and procedure is to provide our patients who suffer from chronic pain, with all the effective treatment alternatives available to help cure or relieve their suffering. As will become evident, the literature supports the use of low dose ketamine infusions by offering a non-opioid option for the management of chronic pain. Because there is no universally accepted clinical protocol, HSSC must develop its own set of policies and procedures for the administration of ketamine. This will be based upon the best practices distilled from the literature reviews and will require identification of the appropriate dosing, length of time for infusion, patient selection, concurrent use of other medications, monitoring and staffing.
Based upon the literature, and the clinical experience of the HSSC ‘s IPS providers, the physicians, and Pharmacy Improvement Committee (PIC) have approved ketamine infusions for use in chronic pain inpatients; and have determined it to be a safe and effective treatment modality. In addition, a review and analysis of the Federal Drug Administration’s (FDA) position on the use of sub-anesthetic doses has been completed. The FDA has identified ketamine as an intravenous anesthetic; however, its off-label use as an analgesic has been expanded to include its usage in moderate sedation. Regarding its use in chronic pain, the FDA still considers this application as experimental and because it is an anesthetic, it must administered licensed trained anesthesia providers.
Following the literature review, a determination has been made to administer these infusions in the post anesthesia recovery area (PACU). The PACU is a critical care area with staff trained in advanced cardiac life support (ACLS). In addition, all necessary monitoring and rescue equipment is available and the staffing ratio is one nurse to two patients. The specific PACU selected has an anteroom, which will provide a quiet environment where the lights can be dimmed, and staff traffic and noise is minimal. Though this is an ideal environment, it presents a very different patient population for PACU nurses. These patients are non-surgical medical cases, who will be receiving infusions lasting any where from three to six hours. The focus of staff education will be to alleviate concerns relative to the administration process, patient monitoring, knowledge relative to the mechanism of action, treatment of side effects, and recognition of adverse reactions. PACU nurses are well trained and equipped to manage conscious sedation, however, historically their experience does not include managing long-term infusions of a low dose anesthetic. It is necessary to emphasize, that administering this treatment to this population, will provide some patients with the first real significant relief from their pain condition.
This project represents a top down approach, and thus inherent in this approach, is the presence of a power-coercive effect. However, an empirical-rational strategy will also be embedded. This will emphasize the importance of providing the requisite education and information to ensure the nurses are safe and confident in providing this treatment. In addition, a reduction in patient suffering will also provide both cognitive and emotional gratification for the nurses caring for these patients. For this reason, it is important to specifically identify those nurses who are informal leaders and early adopters and to educate them relative to the need and importance of ushering in this practice change. The introduction of ketamine infusions necessitates a one to one nursing ratio, which can increase the stress of the staff. Thus, if a nurse is providing care to one patient for a period of three to six hours, this effectively adds to the workload of the other staff and increases the nurses’ insecurity when staffing is inadequate to cover the needs.

Chapter II: Review of the Literature
B1. Credible Sources
An extensive literature search and identification of common themes proffered by the researchers is required to best prepare for the implementation of a ketamine infusion protocol and nursing process at HSSC. This will permit a much greater understanding of the current science, clinical applications, pharmacology and safety profile of ketamine. In addition, information will be obtained from other institutions currently providing this treatment. Clinical studies performed and expert opinions will inform what resources are needed, the criteria for appropriate patient selection, safe administration, dosing, length of infusion time, concurrent use of medications to ameliorate common side effects, and adverse reactions, which may occur during an infusion.
Please see Appendix A on page 29 (The Credible Sources Table). The information contained in this table provided the evidence used to inform the process development and rationale for HSSC’s adoption of this modality. Search engines included, Google Scholar, OVID, and PubMed:
Key words: ketamine, chronic pain, pain management, pain burden, ketamine’s safety profile, N-Methyl-D-Aspartate antagonists, nursing care with ketamine infusion.
B2. Best Practices
The best practices identified from the literature are:
1) The use ketamine to treat chronic pain exacerbations refractory to conventional treatments is effective and should be available for this population. It is believed that because of its specific NMDA receptor affinity, it is an effective and proper choice for the treatment of chronic pain (Brevik, et al., 2013; Connolly, et al., 2015, p.943; Johannes, et al., 2012, p. 1230; Kennedy, et al., 2014, p. 983; Leung, et al., 2016, p. 5: Olsen, et al., 2016; Patil & Anitescu, 2012, pp. 264-265; Pickering, & McCabe; 2013, p. 233-238; Peltoniemi, et al., 2016, pp. 1059-1063; Zhao, et al., 2018).
2) The use of low dose ketamine infusions in chronic pain states requires dosages less than anesthetic levels. In addition, continuous infusions lasting several hours is recommended (Gorlin, et al., 2016, p. 160; Jouguelet- Lacoste, et al., 2015; Kurdi, et al., 2014, p. 283; Polomano, et al., 2013, pp. 1088-1092; Xu, et al., 2016; Zhao, et al., 2018).
3) The use of anxiolytics to counteract ketamine’s common side effects is roundly recommended by the researchers (Azari, et al., 2012; Golembiewski, 2017, p. 660; Leung, et al., 2016, p. 5; Niesters, et al., 2013, p. 357).
4) Providing 1:1 ACLS trained critical care nursing to administer these infusions in an environment with hemodynamic monitoring, rescue equipment, and direct supervision by trained license anesthesia providers also recommended (Carlson, 2014; Polomano, et al., 2013, p. 1090; Olsen, et al., 2016).
B3. Evidence Summary
In reviewing the evidence, several key areas of agreement are identified. These areas of consensus will inform a comprehensive and safe process for the administration of low dose ketamine infusions in the PACU at HSSC. As consistently recommended in the literature, ketamine can reduce pain in patients who suffer from chronic pain. In addition, the literature provides specific information relative to appropriate sub anesthetic dosing; the rationale for providing longer infusion times; inclusion of anxiolytics (benzodiazepines and clonidine) to mitigate psychomimetic and physiological side effects; ketamine’s safety profile; and the necessity for careful monitoring during ketamine infusions. These areas of agreement and recommendations by the researchers provide a framework for identifying the best practices to be adopted by HSSC. Despite the absence of a universally accepted clinical protocol or guideline, these best practices reflect that this procedure/process, which has been researched extensively, has verified optimal results, and therefore is determined to be accepted as an effective treatment.
Improved Pain Scores with Sub Anesthetic Infusions of Ketamine
There is a vast amount of information relative to the use of Ketamine for treating chronic pain. However, the outstanding issue remains that as late as 2017, there is no clinical treatment guideline that is universally accepted (Jonkman, et al., 2017, p. 5). Every journal article reviewed found that infusions of ketamine administered in sub anesthetic dosages were effective in reducing chronic pain. Universally the consensus is that the drug’s specific action at the NMDA receptor site is the reason for its ability to reduce chronic pain, and according to Peltoniemi, et al., (2016, p. 1065) and Cossins, et al., (2012), ketamine is the most potent NMDA antagonist available and able to provide statistically significant reductions in pain. Therefore, in and of itself, the use of ketamine to treat chronic pain is a best practice.
The following research articles all concluded that ketamine provided relief and reduction in pain scores.
In the works, of Niesters, et al., (2013, p. 358), and Patil, et al., (2012, p. 267), they concluded ketamine a useful tool in the treatment of chronic pain refractory to conventional modalities. However this was not consistently reproducible. Both researchers agreed the success of ketamine was directly attributed to its effect on the NMDA receptor sites, and therefore a potentially more efficacious treatment modality than reliance on opioid or other conventional therapies (Peltoniemi, et al., 2016, p. 1070; Zhao, et al., 2018). In other studies, those conducted by Connolly, et al., (2015, p. 954), Niesters, et al., (2013, pp. 359-360), and Xu, et al., (2016; Zhao, et al., 2018), also concluded that ketamine was an effective modality in treating chronic pain. In addition, Jouguelet-Lacoste, et al., (2015, p. 383) found that with the use of low dose ketamine infusions, opioid consumption could be reduced by 40% percent. Effective treatment of chronic pain requires a long-term plan. The use of opioids was never intended to be a long-term solution for pain management. For many reasons, the ability to reduce a patient’s need for opioids is critically important in their rehabilitation.
As previously mentioned, a distillation of the current literature does not coalesce into a specific treatment guideline or clinical protocol. However, when faced with conventional therapy alternatives, Niesters, et al., (2013, p. 364) found that only 30%-40% percent of patients with chronic pain obtain pain relief with conventional treatment. Thus because of its specific affinity for the NMDA receptor, it should be considered a viable alternative.
A lack of definition for the “sub-anesthetic” dosing of ketamine is another complicating factor in both the treatment of patients and in the research trials. Because ketamine is an anesthetic, some researchers recommend that ketamine infusions be reserved for only severe cases involving chronic refractory neuropathic pain Azari, et al., (2012). Connolly et al., (2015, p. 953); Niesters, et al., (2013, p. 364); also concluded, that the clinical trials and meta analyses, reviewed were plagued with heterogeneity in dosing, length of infusion, patient selection, sample size, and otherwise methodologically flawed. Thus, the consensus has been weak or inconclusive in support of ketamine as a front line treatment. Which according to Tighe, et al., (2015, p. 1821) may not be the best strategy because in the majority of cases chronic pain evolves from acute pain.
Another confounding finding involves the relationship between chronic pain and physical mobility and function. Again, the study results are inclusive. Though all researchers concur that pain relief was achieved, functional ability did not always improve. In many cases this can be attributed to the length of time the patient has been in pain. Following an injury, loss of function can occur in a relatively short period, and in individuals who have suffered for long periods, functional loss may become permanent. There is little agreement to suggest that an inverse relationship exists between pain mitigation and increasing function (Niesters, et al., 2013, p. 366; Patil & Anitescu, 2012, p. 265; Schidler, et al., 2013; Sleigh, et al., 2014). In a randomized double blind placebo controlled trial conducted by Schidler, et al., (2013), they found that changes in motor function were mediated by with changes in pain intensity, rather than motor changes influencing pain scores. And finally, pain reduction; regardless of how it is achieved, can potentially improve motor function, which is an important goal in the management and rehabilitation of movement disorders secondary to chronic pain.
Dosing and Length of Infusion Times
Ketamine is an anesthetic, however as noted above there has been extensive interest in the use of this medication in sub-anesthetic dosages. Currently the anesthetic dose is >1mg/kg. Though there is no clear definition of sub anesthetic dosing, an accepted starting point is believed to be 0.1mg/kg to 0.5mg/kg (Gorlin, et al., 2016, p. 162; Jouguelet- Lacoste, et al., 2015; Polomano, et al., 2013, p. 1092; Kurdi, et al., 2014, p. 283; Lee & Lee, 2016; Maher, et al., 2017, p. 663; Xu, et al., 2016). This is not the universally accepted standard for sub anesthetic dosing, but it falls close to the acceptable range. As seen in the literature clinicians and researchers employ different dosages and length of infusion times.
There remains a dearth of data regarding the pharmacokinetic implications of sub-anesthetic ketamine infusions (Gorlin, et al., 2016, p. 162: Golembiewski, 2017, p. 660). According to the literature, the dosages used in these studies ranged from 0.1mg/kg to 1mg/kg and the duration of infusions ranged from one hour to 100 hours of continuous infusion. Most of the studies employed three to five hour infusions given consecutively over several days. We can appreciate that with such a variation in a clinical trials it is difficult to develop a protocol. Clinical trials reported by Kurdi, et al., (2014, p. 285); Jonkman, et al., (2017, p. 5); Maher, et al., (2017, p. 663), all reviewed studies with varying dosages and infusion administration times but all were low dose infusions with a range maintained below anesthetic levels.
The length of infusion and dosing has become a critical point in the development of the nursing process at HSSC. The Director of Pharmacy and the Director of the Inpatient Pain Service have agreed upon the appropriate parameters for these infusions. Following a synthesis of the literature they agreed upon a dosage range of 0.1mg/kg to 0.5mg/kg. These infusions will be administered over a period of three to six hours.
Concurrent use of Anxiolytics
Ketamine is noted to have a constellation of side effects, which are believed to be dose dependent. The effects are both physiological and psychomimetic. Common physiological effects seen at both anesthetic and sub-anesthetic dosages include, increased heart rate, increased blood pressure and cardiac output, increased salivation, increased intraocular and cerebral pressure and nystagmus. Even at anesthetic dosages ketamine preserves respiratory integrity and drive. However, though rare in sub-anesthetic dosages, increased salivation, can lead to laryngospasm, which requires emergency intervention.
Other significant side effects cited by the authors, were related to potential psychomimetic effects, which in sub-anesthetic dosages can range from bad dreams, increased anxiety, panic attacks, and visual and or auditory hallucinations. Indeed one of the contraindications to sub-anesthetic ketamine infusions is active psychosis or a psychiatric history of schizophrenia and/or paranoia. The following researchers, Leung, et al., (2016, p. 7) Gorlin, et al., (2016, p. 162); Xu, et al., (2016); Maher, et al., (2017, p. 665); and Kurdi, et al., (2014, p. 285), have all recommended the use of anxiolytics or benzodiazepines to be administered prior to and during a ketamine infusion to reduce both the physiological and psychomimetic side effects associated with the sub-anesthetic dosages used in ketamine infusions.
Ketamine’s Safety Profile, Pharmacokinetics, and Monitoring During Infusions
As this will be a new process for the IPS team, it is important to fully understand the mechanism of action of ketamine, its side effects, adverse effects and contraindications in order to provide a comprehensive training program for the staff. The Director of Pharmacy and the IPS Director agreed upon dosing and length of time for infusions. Initially the IPS wanted higher dosing which the pharmacy thought approached anesthetic levels, which would not only preclude nurses managing the infusions but would pose increased the risk to the patients. As mentioned previously, the definition of sub-anesthetic dosing remains somewhat allusive.
For the chronic pain population, ketamine is well tolerated when used in conjunction with benzodiazepines. Ketamine’s chemical structure is closely related to phencyclidine (PCP), and unfortunately the general public has abused it as a recreational hallucinogen. Niesters, et al., (2013, pp. 365-367) analyzed ketamine’s safety profile by dividing the side effects and adverse reactions into two subsets, the central nervous system (CNS) and the cardiovascular. They described the CNS effects as largely psychotropic, resulting in multiple reactions, from anxiety to auditory and visual hallucinations. Though many of the side effects are believed to be dose dependent, even in the low-dosages these effects can occur (Leung, et al., 2016, p. 8). The cardiovascular effects result in increased heart rate, blood pressure, tachyarrhythmias, increased cardiac output and increased myocardial oxygen requirements; this response is the result of a system-wide activation of the sympathetic nervous system and inhibition of the vagus nerve.
Given the potential adverse reactions, careful monitoring of these patients is essential (Niesters, et al., 2013, p. 366: Leung, et al., 2016, p. 8; Kurdi, et al., 2014, p. 285: Polomano, et al., 2013, p. 1094). As mentioned above, the use of the anxiolytic midazolam a benzodiazepine is universally recommended to mitigate most of the medications negative side effects.
To date there has not been a significant amount of study done one the opioid sparring effects of ketamine. In a study conducted by Jouguelet, et al., (2015), they were able to quantify the reduction in the need for opioids by 40% percent with the use of ketamine. Though this study was aimed at the use of ketamine in the postoperative period, it is important consider in the management of chronic pain patients as well. Short-term use of opioids typically is not of serious concern. However any decreased use of opioids in the chronic pain population is beneficial, as the side effects of these drugs are unpleasant. Bowel obstructions, opioid dependency, and increasing tolerance are all problematic for the chronic pain population.
Monitoring Recommendations During Ketamine Infusions
The necessity for continuous monitoring of ketamine infusions is universally recommended. There is no question, that given the CNS and cardiovascular effects, close monitoring must be provided. Ketamine has the potential to cause significant and unpleasant potentially life threatening reactions (Leung, et al., 2013, p. 6: Carlson, 2015: Niesters, et al., 2013). In a review done by Leung, et al., (2013, p. 7) however, these authors proffered Ketamine’s wide margin of safety even when overdoses inadvertently occurred in a clinical environment that ended without any significant adverse events (SAEs). In another single institutional retrospective review conducted by Polomano, et al., (2013, p. 1097), the authors reported administering ketamine infusions continuously for three-days at dosages of < 0.12mg/kg/hr. The first four hours of treatment took place in the intensive care unit (ICU), staffed with one to one nursing. At the completion of four hours, the patients were moved to a general ward for the remainder of the 3-day infusion. Per their study they did not experience any SAEs. This study was conducted at Walter Reed Army Medical Center in Washington, DC with 19 patients who had suffered a myriad of traumatic limb injuries with significant neuropathic pain, and who were unable to obtain adequate pain relief with conventional therapies. What is interesting in this study is the determination that specifically after four hours, if no untoward effects were seen, the patient could be sent to a general ward without the specialized monitoring.
The goal of HSSC is to develop a systematic procedure/process to assure the safety of patients while providing the ketamine treatment. Though some variation exists, the literature recommends these patients be continuously monitored in a critical care area for the duration of the infusion by specially trained nursing staff. This includes, hemodynamic monitoring with heart rate and rhythm, blood pressure, pulse oximetry and in some instances entidal CO2 monitoring. In addition, pain scores, frequent assessments for nystagmus, hallucinations and panic attacks must be conducted and documented (Leung, et al., 2013, p. 11: Carlson, 2015: Niesters, et al., 2013, p. 365-366).
C. Recommendations
Chronic pain is a national epidemic. As discussed previously, prevalence statistics in United States, report that 50 to 100 million people suffer from this condition (Kennedy, et al., 2014, 983: Gaskin & Richard, 2012, p. 718). Many report either frequent or persistent symptoms, or pain that is excruciating and unbearable. As medical and nursing providers, it is important to realize we are professionally and morally responsible for providing relief to those that suffer. Many of these patients have been maligned or marginalized over the years as drug seekers and malingerers. We owe it to our patients and society to continue searching for relief of their suffering. Considerable evidence based on science and best practices have been postulated in the treatment of chronic pain but there is still much more that needs to be done.
In review of the literature, many of the studies, though methodologically flawed and heterogenic, a consensus emerges regarding ketamine’s effectiveness in reducing pain in refractory neuropathic conditions. Ketamine is a well-established schedule III controlled substance and an FDA approved anesthetic (Carlson, 2015). Ketamine is classified as a dissociative anesthetic that produces a cataleptic condition with profound analgesia and amnesia. Though ketamine was introduced in the early 1960’s, there is burgeoning interest in its analgesic effects when administered in sub-anesthetic dosages. Per Niesters, et al., (2013, p. 359) there is evidence supporting recognizable changes in the physiology and structure of central sensitization in chronic pain states, and researchers have concluded that ketamine’s efficacy in the treatment of chronic neuropathic pain is evident. The purpose of this project is to develop a specific and innovative pain management offering to be part of an overall HSSC strategy to establish a multi-disciplinary pain management program. Heretofore, in the treatment of chronic neuropathic chronic pain, with sub-anesthetic dosages of ketamine had not been administered at HSSC.
It is important to speak to the prevalence of chronic pain, the cost to society and the medical provider’s responsibility in identifying the most cost effective and efficacious treatment for this condition. As noted earlier, chronic pain is one of the major reasons why patients seek medical treatment. As an institution of healing, it is HSSC’s obligation to provide access to effective treatment regimens for the community we serve. As noted earlier, patients entering the emergency department, require relief from their symptoms and require more effective options than opioid prescriptions.
The articles by Gaskin & Richard, (2012, p. 720) and Brevik, et al., (2013) and the IOM, (2012), articulate the scope of the problem. These articles do not discuss specific treatment modalities, but quantify the problem as a major health issue. Brevik, et al., (2013) stresses the need for the creation of integrated and interdisciplinary pain management programs. Gaskin & Richard, (2012, p. 723: Kennedy, et al., 2014, p. 984) provide data that illustrates the significance of the problem by affirming that millions Americans suffer from chronic pain.
It is critical that we develop treatment plans for individuals suffering from persistent pain and impaired functional status. For many of these patients, completing the activities of daily living is sometimes impossible and the ability to provide for their families and themselves impacted. The cost of lost productivity, absenteeism, and early retirement, affects not only the individual but also society as a whole, and according to Brevik, et al., (2013) and Olsen, et al., (2016), the impact is grossly underestimated. Many of the studies recommended the need for well-designed randomized placebo controlled trials to evaluate the efficacy of treatment interventions for chronic pain. In addition, a cost analysis for developing comprehensive programs to address the condition is overdue (Azari, et al., 2012; Schidler, et al., 2013). These authors proffer that patients suffering with intractable chronic pain should have full access all evidenced based diagnostic and therapeutic modalities. At HSSC, the introduction of inpatient ketamine infusions is a start.
In review of the literature, the following best practices will be incorporated into the development of the nursing process at HSSC. The first best practice that will be adopted by HSSC is the introduction of ketamine into IPS arsenal for treating chronic pain. To review, chronic pain is a product of central sensitization identified at the NMDA receptors (Pickering, & McCabe, 2013, p. 234). This prolonged receptor activation results in plasticity changes in the brain and spinal cord creating a central sensitization. Ketamine has shown to modulate these neural receptors, resulting in the diminution of pain impulses. In addition, ketamine has been shown to reduce the need for increasing dosages and tolerance of opioids in these patients. It is believed that ketamine is best in the treatment of central sensitization (Pickering, & McCabe, 2013, p. 235).
Review of the literature informs the best practice in sub anesthetic dosing and length of infusions. Based upon these recommendations an agreement was reached by the Director of Pharmacy and the IPS Medical Director to use dosages of 0.1mg/kg to 0.5mg/kg for a period of 3 to 6 hours. Provided the treatment is well tolerated, these infusions will be administered over several consecutive days. Kurdi, et al. (2014, p. 288) studied patients receiving dosages of 0.25 mg/kg to 0.5 mg/kg over 4 to 5 for five consecutive days and found a 21.4% decrease in pain levels as compared with the placebo group. The systematic literature review performed by Maher, et al. (2017, p. 665) suggests the low dose ketamine range to be between 0.1mg/kg to 0.5mg/kg, which is being adopted by HSSC.
To reduce ketamine’s side effects, the best practice cited in the literature has been the use of Midazolam and Clonidine administered during the infusions. Midazolam /Versed is a benzodiazepine, and Clonidine, is a centrally acting alpha-agonist, hypotensive agent, and anxiolytic. Both of these medications act to reduce the sympathetic nervous system response and work synergistically to control the potentiation of hypertension, tachyarrhythmias, nystagmus, anxiety, and hallucinations both auditory and visual (Maher, et al., 2017, p. 668).
Close monitoring is the standard of care in the administration of low dose ketamine. The literature recommends these patients be monitored either in an intensive care unit or recovery area. Carlson, in her (2012) advisory opinion, published in by the Nursing Care Quality Assurance Commission (NCQAC) identifies the competencies, policies, procedures, patient monitoring and resuscitation equipment needed when administering ketamine in sub anesthetic dosages.
The PACU is the chosen area for these infusions because of the availability of a separate anteroom complete with all necessary monitoring and rescue equipment, and an automatic door separating it from the main PACU. The area is quiet with dimmed lighting to provide the safest and best possible experience for the patient. Though benzodiazepines assist in mitigating the psychotropic effects, decreased noise and light are also necessary to reduce environmental stimuli that can cause excitation and contribute to anxiety. Though some variation exists, the literature recommends these patients should be continuously monitored in a critical care area for the duration of the infusion by specially trained nursing staff. (Carlson, 2015: Leung, et al., 2013, p. 11: Maher, et al., 2017, p. 670: Niesters, et al., 2013, p. 367).
In conclusion, patients with intractable chronic pain are left with few treatment options. At HSSC we are committed to providing a full range of treatment modalities. Despite the lack a treatment protocol for the administration of ketamine in this population; and the lack of clarity when defining chronic pain, or appropriate dosages, and infusion times, the evidence presented in the literature speaks volumes about the potential positive benefits that can be provided to these patients. Though all agree more work needs to be done, this treatment will be available in our community.

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Cossins, et al., 2012 Google scholar,
PubMed, Cochrane Register of Controlled Trials Yes Yes I Systematic review of study trials addressing the efficacy of many different pain management modalities employed in the treatment of CRPS. This study used a classification of positive, if a statistically significant reduction in pan was achieved, and negative if otherwise. Our focus that of ketamine’s efficacy was discussed. The two small RTCs reviewed in this article, (Sigterman and Schwartzman) were both classified as positive in demonstrating ketamine’s statistically significant ability to reduce pain. However, the authors conclude that any medicinal/medical modality employed to treat CPRS pain refractory to conventional treatments has not demonstrated sustained performance and therefore larger, multi-center and with longer follow-up investigations must be done. This article supports use of ketamine because in their study they found a statistically significant improvement in pain with its use.
Yes
Gaskin & Richard, 2012 Google Scholar, surveys conducted by MEPS, AHRQ, & NCHS Yes Yes VII This focus article attempts to quantify the health care costs associated with pain, and the annual costs attributable to lower worker productivity. The authors concluded that the total costs ranged from $560 to $635 billion in 2010. The healthcare costs alone were $261 to $300 billion for the treatment of pain. In addition, they found that these costs exceeded the annual costs for the treatment of heart disease ($309 billion), cancer ($243 billion and diabetes ($188 billion). The authors added that these were conservative estimates and did not include costs associated with pain treatment for residents in nursing homes, or those people incarcerated or in the military. This article supports appropriate patient selection is employed, specifically for patients with intractable chronic pain. Yes
Azari, et al., 2012 Google Scholar,
PubMed Yes Yes I The objective of this article was to identify published studies that demonstrated the efficacy and safety for the use of ketamine in treating patients with CRPS. Nine studies were reviewed and in conclusion the ability to compare results was thwarted by, differences in study design. Specifically, different criteria were used in patient selection, differing ketamine dosages, and routes of administration, small sample sizes, and use of medications given concurrently with ketamine. In conclusion the authors could not recommend the routine use of ketamine for treatment of CRPS, and thus the need for large, well designed, and application of strict criteria, randomized placebo controlled trials be conducted. This article supports the need for clinical trials with the use of ketamine fin treating chronic pain. Yes

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Institute of Medicine, (IOM), 2012 Google Scholar No Yes VII This report brief issued by the Institute of Medicine (IOM), underscores the chronic pain epidemic in the United States. With the passage of the Affordable Care Act (ACA) in 2010, which required the Department of Health and Human Services to solicit the IOM to study pain as a public health problem. This was to include, current pain science, care, treatments, education and to make recommendations to move forward. The IOM published Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research, which outlines their finding and recommendations. These include, that state and federal agencies collectively gather information about the incidence, and prevalence of pain. In addition the National Institutes of Health is accountable for taking the lead in moving pain research forward by fostering coordination across institutions and identifying best practices. This article is a call for action due to the prevalence chronic pain nationally and supports the need to use innovative approaches to solve the problem. Yes
Johannes, et al., 2012 PubMed, Cochrane, Google Scholar Yes Yes VII This Journal of Pain article is a cross sectional internet based survey was conducted to estimate the prevalence of chronic pain in the United States. The survey was distributed to 35, 718 Americans, ages 18 and older. Reponses were obtained from 27, 035 adults. The criteria for inclusion were chronic pain, recurrent pain and pain lasting for 6 months or longer. In addition the pain severity of this group ranged from 4 to 10 on a visual analog scale (VAS) of 0 to 10. Chronic pain prevalence was found to be 30.7% in this survey; of that 89% reported experiencing pain for a year or more and 86% reported they experienced pain at least 2 to 3 times per week. The authors cited that chronic pain in America and around the world is a major health concern and one of the most frequent reasons for seeking medical treatment. All of this indicates that individuals suffering chronic pain have a significant reduction in quality of life. The definition of chronic pain remains allusive. Thus when studies are conducted, clear definitions must be applied to ensure appropriate patient selection. This article outlines the significance of chronic pain in the United States and supports the need to provide effective treatment to address the financial and clinical impact on chronic pain sufferers.

Yes
Patil & Anitescu, 2012 Google Scholar, OVID Yes Yes III Retroactive analysis of University of Chicago’s Medical Center database for Ketamine infusion cases over five-year period. Case selection resulted in 49 cases of chronic pain patients, who had undergone a total of 369 infusions. Mean duration of pain history 5.62 years, however some for only 6 months. Authors hypothesized, that based upon their clinical experience, Ketamine could provide relief of intractable pain for a variety conditions. The strength of the study lies in the ability of the providers to control their experiment. The following limitations were noted; this was a one-center trial, there is no data supporting their long-term pain relief findings. However, they concluded that based upon post-infusion phone calls and medical records, this was the case. They stated that half their patients had relief, improved functionality and exercise tolerance for up to 3 weeks. This runs contrary to many subsequent studies. This study if better designed supports the use of Ketamine and its efficacy in the treatment of chronic pain. This article also provides an explanation of ketamine’s effect on the central sensitization. This article supports the best practice of using ketamine in the treatment of chronic pain due to its effect on central sensitization.
Yes

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Polomano, et al.,
2013 Google Scholar
PubMed Yes Yes IV A retrospective case series review of veterans conducted at the Walter Reed Army Medical Center in Washington DC. The study consisted of 19 inpatients suffering neuropathic pain from severe limb injuries refractory to multimodal analgesia. These patients were administered low dose infusions for a 3-day consecutive period, with dosages equivalent but not to exceed 120ug/kg/, which translates to 0.12mg/kg. For the first four hours of the infusion they were monitored as 1:1 either in the ICU or PACU. After four hours, they were sent to the general ward for the remainder of the treatment. This small retrospective study demonstrated reduced pain scores over the three-day period and decreased opioid need. The authors concluded that the results may have been more dramatic with longer infusion periods. In addition, the subjects in this study were given their routine or as needed opioid during the therapy sessions and no attempt was made in maintain the consistency of care. In addition, this inpatient population was subject their continued treatments which necessitated, dressing changes, wound care, and stump debridement, all of which would exacerbate. This article supports best practice of close monitoring of patients receiving ketamine infusions., recommending the ICU or PACU for the infusions. Yes
Niesters, et al., 2013 Ovid MEDLINE. PubMed Yes Yes VII This article provides an excellent overview of the history of use, pharmacology, uses, potential benefits and risks associated with the use of ketamine in the treatment of chronic pain. The authors conducted extensive literature review. They proffered that only 30-40% of chronic patients obtain relief from the conventional treatment modalities of opiates, anti-depressants, anti-epileptics. They cite the increasing use the anesthetic Ketamine at sub-anesthetic doses to treat therapy resistant chronic pain syndromes especially those with a neuropathic component, such as complex regional pain syndrome, post- herpetic neuralgia, and neuropathic pain from peripheral nerve damage. The authors provide an excellent discussion regarding the pharmacokinetics and pharmacodynamics of ketamine and supporting rationale for its use in the treatment of chronic pain. However, they state that, though pain relief has been achieved, the period of pain relief, and functional improvement has not been adequately quantified. In addition, the inpatient setting is expensive and multiple resources must be utilized. The authors also proffer that the length of time of infusion maybe directly related the length of time the patient has relief. The authors also recommended the use of benzodiazepines (midazolam) and close monitoring of vital signs is mandatory. Without additional RCT’s, they concluded the use of ketamine should be restricted to patients with severe neuropathic pain resistant to conventional therapy. This article also raises questions relative to ketamine’s relatively short half-life when compared to its continued ability to relieve pain. The article supports the use of ketamine given that most of these patients only have a 30% to 40% improvement in pain with conventional modalities. Also supports best practice of using benzodiazepines. Yes

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Pickering, & McCabe, 2013 Google Scholar Yes Yes VII This article is a commentary. It was published in the British Journal of Clinical Pharmacology at the same time as the article noted above. These authors contend ketamine’s NMDA channel blockade properties, induce synaptic potentiation, and modulates NMDA receptor’s role in pain sensitization. Ketamine is also known to act on nicotinic and opioid receptors as well, and is believed that its analgesic and anesthetic effects are mediated by NMDA receptor antagonism. A review by the authors of several studies involving long term (5 to 10 days) of sub anesthetic ketamine infusions demonstrated a reduction in pain lasting weeks beyond the treatment period. The article also addresses the use of ketamine infusions in the treatment of CRPS, which is a significant clinical problem, with limited therapeutic options. They raise the question, can ketamine be used as an evidenced-based cost-effective, rational, safe and practical therapy for CRPS. It supports the rationale for the use of ketamine in chronic pain because of its specific action at the NMDA receptor site. In addition it supports its use to provide longer periods of relief.
Yes
Brevik, et al., 2013 OVID, PubMed,
Google Scholar Yes Yes VII This article discusses the financial ands social impact of chronic pain conditions in Europe. The authors contend the burden of chronic pain placed on individuals and society at large is equal to or greater than other health care priorities. Chronic pain markedly decreases the quality of life for both the victim and their families. It interferes with activities of daily living, home responsibilities, sleep patterns and personalities. They recommend that patients suffering from chronic pain should have access to all diagnostic and therapeutic modalities. The authors cite the heterogeneity; variable quality, patient selection, and participant follow-up in trials conducted have provided little in identifying best practices or creation of multidisciplinary programs to provide long term benefit. They further recommended that fully integrated interdisciplinary pain programs be created and be readily available for patients diagnosed with chronic pain syndromes. This article discusses the impact that chronic pain has on individuals and society, and supports the premise that these patients have access to all treatments, which have shown promise. Yes
Schidler, et al., 2013 Google Scholar, OVID Yes Yes II This article describes a randomized double blind placebo controlled study conducted over a 12-week period with 60 CPRS patients. The authors found that pain intensity and motor function were directly related. Their results showed that changes in motor function were related to pain scores irrespective of whether the patients received ketamine or placebo. Ketamine did not demonstrate direct effect on motor function as assessed over the 12-week period. The researchers wanted to evaluate the potential pain-relieving effect of ketamine or placebo. Their findings suggested that changes in motor function were medicated by with changes in pain intensity rather than motor changes influencing pain scores. And finally, pain reduction; regardless of how it is achieved can potential improve motor function. Thus achieving pain relief should be an important goal in the management of movement disorders. This article supports the relationship between improving pain and improving function and the need for clinical trials with the use of ketamine for that purpose. Yes

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Kennedy, et al., 2014 Google Scholar Yes Yes VII This article attempts to quantify the prevalence of persistent pain in the United States. They rely on data collected from the Quality of Life/Functioning and Disability Supplement (QOL), the Medical Expenditure Panel Survey (MEPS), the National Health and Nutrition Examination survey and the National Health Interview Survey (NHIS). In 2010 the findings showed that 19% (= 39.4 million) of Americans reported they suffer from persistent pain. Persistent pain was self-reported and defined as occurring every day or most days over the preceding 3 months. Of the 39.4 million Americans reporting, 67.2 reported their pain as constantly present and 50.5% reported their quality of pain as excruciating and unbearable. And of these patients only 28.2% feel that their pain is alleviated completely by the medications prescribed. The authors proffer that from a public health perspective persistent pain can be an indicator of the unmet need for pain management in the general population, and the continued risk to this population for disability, depression and dependency. The authors attempt to quantify the prevalence of chronic pain, and that these patient do not have adequate relief with traditional treatment modalities which supports the use of ketamine as an option.
Yes
Sleigh, et al., 2014 Google Scholar,
OVID Yes Yes VII This article is a review of the pharmacological actions of ketamine. It identifies the agent as a dissociative anesthetic. Which produces a hypnotic state, and in addition provides profound analgesia, increased sympathetic activity and maintenance of respiratory function. Which historically has made this drug, the agent of choice on the battlefield and in emergency departments. At a molecular level, once glutamate has been released from the NMDR receptor site, ketamine remains trapped in the now closed ion channel, which creates prolonged blockade, disrupting physiologic and pathologic function. What is most interesting about ketamine, is the clinical benefits that remain, long after the drug has been excreted. Of interest, the authors holders of patent, that is related to a ketamine derivative. Yes
Kurdi, et al., 2014
PubMed,
Google Scholar Yes Yes VII This article is an essay, which discusses the current uses of ketamine. It describes the pharmacological actions of the drug and the physiological response. Ketamine stimulates the cardiovascular system. it is both a inotropic and chronotropic agent, increasing cardiac output and blood pressure, medicated through the sympathetic nervous system. It has cataleptic, amnesic, analgesic, and dose dependent anesthetic actions. It’s dissociative state is characterized by an awake patient who is detached from the situation. When providing low dose ketamine infusions, the authors concluded dosing should be 0.25mg/kg to 0.5mg/kg. In one RCT cited, patients suffering from CRPS received ketamine infusions over a 4 to 5-day period demonstrated a 21.4% decrease in pain as compared to the placebo group. The authors raised concerns about the relative contraindications, including: active psychosis, hypertension, increased intraocular pressure, tachyarrhythmias, kidney and liver disease. And as cited by many, ketamine has a potential for addiction. They recommend also the clonidine and midazolam be given concomitantly. They attempt to define “low dose” ketamine, and provide recommendations for dosing for ketamine infusions. In addition they recommend that it be employed in a pain management program to treat chronic pain. Yes

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Carlson, 2014 Google Scholar Yes Yes VII This article is an Advisory Opinion, produced by the National Care Quality Commission at the bequest of the Department of Health. This opinion has been accepted by the NCQA as an official opinion regarding safe nursing practice. It does not legal binding and is not a regulation or a declaratory ruling by NCQA. It outlines clearly the scope of practice relative to the administration, maintenance of sedating analgesics and anesthetics as prescribed by authorized providers. Under this opinion, nurse must have specialized training and the ability to administer this drug classification safely and competently. In addition they must be able assess the patient’s condition and intervene if and when rescue is required. They argue that there is “no bright line between minimal sedation and anesthesia.” The American Society for Pain Management (ASPMN) supports nursing’s role in the administration and management of patients undergoing treatments involving the use of ketamine. Based upon evidenced based practice the NCQA recognizes the benefit to patients undergoing ketamine treatments for chronic pain. They further describe the competencies, policies and procedures, nursing assessment, patient monitoring, resuscitation equipment that must be available and the medication preparation, administration of and security of controlled substances use. This article recommends the best practices for assessing staff capable of monitoring patients during ketamine infusions, and they recognize the benefits that patients can achieve with ketamine Yes
Connolly, et al., 2015 Google Scholar,
OVID Yes Yes I A systematic literature review, which critiqued the methodological strength of each study. At the outset, the authors were unable find high quality research in this area. The studies were categorized by evidence grade/level. The authors provided only one level I study lead by Azari, et al., 2012, which was specifically designed to address the efficacy of ketamine in the treatment of CRPS pain. The study concluded that ketamine should not be routinely recommended for the treatment of chronic pain. The study conducted by Azari, et al., 2012, was reviewed for this submission. Connolly, et al., 2012, p.943 concluded at the time this article was published that no high-quality evidence was available regarding the efficacy of ketamine in the treatment of chronic pain. He cited the previous work as moderate to low in quality. Problems identified which contributed to this weak showing were related to sample size, study design, differing medication dosages, differing routes of administration, different outcome measures and differing concurrent medication administration during testing. Some investigators have obtained pain relief in newly diagnosed CRPS patients, however negative results in some with long standing disease. This is confounding when the central sensitization of pain is the intended and vulnerable target. Finally, the authors recommend that any intervention that has ameliorated suffering such as experienced by patients suffering from chronic pain refractory to conventional modalities, warrant further serious study. This article illustrates the need for well-designed double blind, placebo controlled, multi-center trials to be done to identify ketamine’s efficacy.
yes

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Jouguelet-Lacoste, J., et al., 2015 Google Scholar,
Ovid Yes Yes I These authors attempted to identify ketamine’s benefits in the management of post-operative pain. Their search of study spanned 40 years, (1966 to 2013). They identified 695 studies for possible inclusion of that 5 were meta-analyses and 39 clinical trials were included, which represented 2, 482 patients, of that 1403 received ketamine. This study provided critical information regarding the impact how ketamine in low dose infusions can reduce opioid consumption by 40% percent and reduces pain scores. The authors found that low dose ketamine continuous intravenous infusions (dosages at < 1.2mg.kg/hr. over 48 hours) did not result in any major complications. This article supports the use of ketamine in chronic pain. Yes
Tighe, et al, 2015 Google Scholar Yes Yes VII This original Research article provides an excellent review of the state of pain treatment and strategies to improve acute pain management. It was a distillation of a of a panel discussion from members of the American Academy of Pain Medicine. It provided a review of identifying and categorizing acute pain from chronic pain. Recommendations identified the following, 1) provide an open source for clinical support tools to assist in clinical decision making, 2) develop strategies for informing and educating third party payers with the intent to reduce the conversion of acute pain to a chronic condition. Supports the need to create clinical decision tools and providing third party payers with the necessary education to see the benefits of appropriate pain management and ultimately provide reimbursement for the treatment.
Yes
Peltoniemi, et al., 2016 Google Scholar,
OVID Yes Yes I This article discusses at length the pharmacodynamics of ketamine and its use in pain therapy. Ketamine is a derivative of phencyclidine and its primary action is on the NMDA receptors within the CNS. It maintains hemodynamic stability by stimulation of the sympathetic nervous system without affecting respiratory drive. It has demonstrated that in low dose administrations it can reduce opioid use and has been effective in postoperative states to reduce opioid use. However the authors advise that its long-term analgesic effects in chronic pain have not been demonstrated. However in numerous studies it has shown short-term analgesic properties in chronic pain syndromes. Ketamine’s unique action is its blockage of the NMDA receptor site. It reduces the frequency and mean opening time of the calcium charnels preventing an influx of calcium. This is important because NMDA receptors are involved with pain transmission and modulation and contribute to central sensitization. According to these authors 10% percent to 50% percent of patients suffer from persistent pain following certain surgical procedures, which they proffer, is caused by iatrogenic nerve injury. As such because of its ability to block NMDA, Ketamine use perioperatively has gained interest in preventing chronic post-surgical pain. In numerous studies ketamine has shown short-term analgesic properties in chronic pain syndromes. Ketamine’s unique action is its blockage of the NMDA receptor site.

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Leung, et al., 2016 PubMed, OVID, Google Scholar Yes Yes I This literature review included 12 meta-analysis/systematic reviews, 4 RCT, 4 open label prospective trials and 5 retrospective studies. Based upon the authors’ literature review, they concluded that in the treatment of chronic pain, ketamine is a relatively safe and promising treatment modality. However, the long-term efficacy, administration route, optimal dosing, and duration of treatment require additional high quality, large, multi-centered placebo controlled, randomized trials. In addition, a cost benefit analysis should be conducted once high quality evidence is identified. Some of the articles listed in this review have been incorporated in this submission. Of repeated concern throughout the literature is the potential for psychotomimetic side effects including agitation, hallucinations, nightmares, anxiety and euphoria. These adverse effects now appear to be largely dose dependent. In the articles reviewed there are significant differences in the dosing, duration of treatment, and settings where the medication is given. Most studies have concluded that the addition of midazolam and or clonidine have been effective in reducing/mitigating negative psychotropic side effects. Supports use of ketamine for chronic pain because of its safety. Also supports best practice of using benzodiazepines Yes
Xu, et al., 2016 Google Scholar,
OVID Yes Yes I A systematic review of the literature on intravenous therapies to determine the level of evidence to guide practitioners in the treatment of CRPS. Out of 299 articles, 101 were deemed relevant, and 63 were chosen for analysis and discussion. Evidence for the use of ketamine in the treatment of CRPS pain was determined to be favorable; however, additional high quality studies need to be conducted, to further evaluate the efficacy, safety and cost-effectiveness. The authors cite a small case study involving 6 patients who received 2 continuous intravenous infusions for 100 hours separated by 16 days, which resulted in elevated liver enzymes in 3 of the patients to 3 times the normal upper limits during the infusions. These levels slowly returned to normal within 2 months after the infusions. The authors also advised that in these studies Midazolam and Clonidine were used during the infusions to reduce any psychomimetic effects. The authors found ketamine to be safe and effective in treating chronic pain. They also highlight the potential for psychotomimetic effects, which are believed to be largely dose dependent and recommend best practice of using benzodiazepines during infusions Yes
Lee, E., Lee, J., 2016
Google Scholar,
OVID Yes Yes I The purpose of the systematic review was to determine whether the analgesic effects of low-dose
(< 0.3mg/kg) intravenous ketamine bolus was equivalent to that of opioids. This article highlights the issue of inconsistent definition of low dose ketamine. The authors proffered that the ketamine blockage of NMDA may improve efficacy of opioids, in addition to prevent serious side effects of opioids, but can also prevent the development of chronic pain which develops with increasing opioids tolerance. This would seem to be an improved first line medication for use in patients with acute pain, the etiology of which may be a precursor to chronic pain. Thus it could be a proactive way to manage conditions whose trajectory endpoint is intractable chronic pain. Serious consideration should given to the location for administration of hallucinogenic agents, of which ketamine’s profile is significant for these events. The efficacy of ketamine in chronic pain is due to its effects on the NMDA receptor sites, making it a good option for people with chronic pain refractory to other modalities. Yes

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Gorlin, et al., 2016 PubMed, Google Scholar,
Yes Yes VII This article is a review of the pharmacology of ketamine, its side effects, sub-anesthetic dosing, and usage in the perioperative area. The authors describe its action on the neurologic, cardiovascular respiratory, gastrointestinal, ocular and psychiatric systems. They identify its action on liver enzymes following sub-anesthetic infusions, warning that increases in liver enzymes, though they quickly return to normal levels at the cessation of the infusions, it may contraindicated in patients with liver disease. Though this article does not specifically address its use in chronic pain, the authors provide a guideline in defining sub-anesthetic dosing at < 0.3mg/kg. However in reviewing many articles this is not consistent. Supports best practices in recommending a specific starting dose Yes
Olsen, et al., 2016 Google Scholar, PubMed Yes Yes IV This was a retrospective and prospective study conducted to identify if a chronic pain protocol could be utilized in the emergency department (ED). The reason for inclusion in this submission is to underscore the frequency with which chronic pain patients utilize EDs for treatment when suffering from an acute exacerbation of their pain condition. This facility resembles HSSC in the location, volume of patients, services provided and location. This article supports the best practice of providing inpatient infusions versus shorter infusions given in the ED to improve patient outcome Yes
Jonkman, et al., 2017
Google Scholar Yes Yes I This systematic review was performed to identify the most current literature on the analgesic efficacy of ketamine in treating pain. Our specific interest is in the treatment of exacerbations neuropathic chronic pain. The authors state that ketamine is in widespread use despite the lack of RTCs and support from medical societies and guidelines. In addition, there remains no consensus on dosing or administration regimen, as sub anesthetic doses are not defined. However, these authors consider dosing of 0.5-0.6mg/kg, with administration durations of 0.5 – I hour as sub anesthetic. The authors believe (as described by many others) that ketamine’s is believed effective because of its action on the NMDR and mu-opioid receptors. In their analysis, they identified 5 descriptive reviews on ketamine for use in treatment of chronic pain. They deemed these reviews as descriptive based upon the heterogeneity between studies. Several of the studies cited by the authors appear in the literature review. Most studies reviewed demonstrated analgesic effects during the administration however only four reported pain relief for greater than 48 hours. This was believed to be attributable to the10-hour infusion period. The authors concluded that a high-quality meta-analysis and trial sequential analysis are required to determine the efficacy ketamine in the treatment of chronic neuropathic pain. These authors support the belief that it is the unique action of ketamine on the NMDA receptor sites that is responsible for its pain relieving effects in chronic pain. Again calling for additional trials. Yes

Authors Database Peer Review Applied Evidence Grade Appraisal Included
Maher, et al., 2017 Medline, PubMed, Google Scholar Yes Yes I Despite multiple studies and extensive use of ketamine infusions there is no consensus on the optimal infusion protocol. Because of this, the ability to conduct a true meta-analysis is not possible. However, the authors outline some important findings: there is level 2 evidence to 1) suggest that longer infusion times of ketamine result in longer periods of pain relief; 2) the total dose of ketamine results in more pain relief and possible longer duration of relief; 3) in most infusion protocols to date, patients experience side effects regardless of rate of infusion, duration of, and total dose administered. The addition of midazolam mitigates these effects. In conclusion, the authors state that the lack of comparative effectiveness studies and different primary end points does not permit direct comparison or optimization of protocols. However, the authors recommend; 1) provide the longest duration of infusion time; 2) dosing should be 0.1 and 0.5mg/kg/hr.; 3) using midazolam to counteract side effects and potentially add additional analgesia. In addition, all infusions should be conducted in a monitored setting under direct physician supervision. These authors support the best practices for longer infusion times and a dosing range of 0.1mg/kg to 0.5mg/kg, and it should be administered with benzodiazepines, and by qualified anesthesia providers and monitored by specialty trained nurses.
Yes
Zhao, et al., 2018 Google Scholar, OVID Yes Yes I This meta-analysis study was conducted to examine ketamine’s efficacy in the management chronic neuropathic pain or CRPS. This article concluded that in the treatment of CRPS, ketamine has been shown to reduce pain for up to 3 months, however again, they concluded that the trials reviewed were heterogenic, and recommended additional well designed studies are needed. In addition they concluded that in patients suffering chronic pain from CRPS there are few treatment modalities, i.e. spinal cord stimulators and sympathetic blocks, which are effective. Thus they recommend that ketamine can provide short-term relief (< 3 months) in many of these cases. Yes

References
Allen, C. A., & Ivester, J. R. (2017). Ketamine for Pain Management—Side Effects & Potential Adverse Events. Pain Management Nursing, 18(6), 372-377. doi:10.1016/j.pmn.2017.05.006
Azari, P., Lindsey D., Briones, D., Clarke, C., Buckheit, T., Pyati, S., (2012)
Efficacy and safety of ketamine in patients with complex regional pain syndrome. CNS Drugs 26 (3), 216 – 228. doi:102165/11595200
Baldwin, M., Boilini, H., Lamvu, G., (2017) Chronic pain and suicide: Is there a role for
ketamine. Military Medicine (182) 11/12, 1746 – 1748. Retrieved from
https://dx-doi-org.miprox.csmc.edu/10.7205/MKME
Blue Advantage Policy #446, (2015). Intravenous anesthetics for the treatment of chronic pain. Blue Advantage Medical Policy #446, [Proprietary Information of Blue Cross and Blue Shield of Alabama]. Retrieved from
https://providers.bcbsal.org/…/Intravenous+Anesthetics…Treatment…Chronic
Breivik, H., Eisenberg, E., & O’Brien, T., (2013. The individual and societal burden of chronic pain in Europe: The case for strategic prioritization and action to improve knowledge and availability of appropriate care. Bio Med Central Public Health, 13, 1-14. doi:1186/1471-2458-13-1229
Carlson, D., (2015). Administration of sedating, analgesic and anesthetic agents. Department of Health: Nursing Care Quality Assurance Commission. Published by the Department of Health [No. NCOA 7.1].
Centers for Medicaid and Medicare, (n.d.). [HCAHPS Scores]. Retrieved from
https://www.medicare.gov/hospitalcompare
Connolly, S., Prager, J., & harden, N., (2015). A systematic review of ketamine for complex regional pain syndrome. Pain Medicine, 16(5), 943 – 969.
doi:101111/pme.12675
Gaskin, J., & Richard, P.(2012, August). The economic costs of pain in the United States. Journal of Pain, 13 (8), 715-724. doi:10:1016/j.jpain.2012.03.009
Golembiewski, J., (2017). Ketamine – what is old is new again. Journal of PeriAnesthesia Nursing, 32 (6), 660 – 663. doi:10.1016/j.jopan.2017.09.003
Gorlin, A. W., Rosenfeld, D. M., & Ramakrishna, H. (2016).
Intravenous sub-anesthetic ketamine for perioperative analgesia. Journal of Anesthesiology, Clinical Pharmacology, 32(2), 160–167. http://doi.org/10.4103/0970-9185.182085
Institute of Medicine, (2012) Relieving pain in America: A blueprint for transforming
prevention, care, education and research. [Report Brief]. Retrieved form https://monkessays.com/write-my-essay/nationalacedemies.org/hmd/Reports/2012/ relieving-Pain-in…. forming-Prevention-Care-Education-Research/Report-Brief.aspx?page=1
Johannes, C., Le, T., Zhou, X., Johnston, J., Dworkin, R., (2012). The prevalence of chronic pain in United States adults: Results of an internet-based survey. Journal of Pain, 11(11), 1230 -1239. doi: 101016/j.jpain.2010.07.002
Jonkman,K., Dahan,A., van de Donk,T., Aarts, L.,Neisters, M., & vanVelzen, M. (2017).
Ketamine for pain. F1000 Research, (6), 1-8. doi: 10.12688/f1000research.11372
Jouguelet-Lacoste, J., La Colla, L., Schilling, D., Chelly, J., (2015). The use of
intravenous infusion or single dose of low-dose ketamine for postoperative
analgesia: A review of the current literature. Pain Medicine 16 (2), 383 – 403.
doi:10.1111/pme.12619
Kennedy, J., Roll, J.M., Schrauder, T., Murphy, S., & McPherson, S. (2014).
Prevalence of persistent pain the U.S. adult population: New data from the 2010 national health interview survey. The Journal of Pain, 15(10) 979 – 984.
doi:1016/j.jpain.2014.05009
Leung, S., Kara, M., Yilmaz, H., Koyuncu, O., Turan, A., (2016). The role of ketamine in
treatment of complex regional pain syndrome: A review of current evidence. Clinical Research in Cardiology. 1(1) 1001 – 1016. ISSN 1861-0684
Kurdi, M., Therth, K., Deva, R., (2014). Ketamine: Current applications in anesthesia,
pain, and critical care. Anesthesia: Essays and Researches, 8 (3), 283-290.
doi:10.4103/0259-1162143110
Maher, D., Chen, L., & Mao, J. (2017). Intravenous ketamine infusions for
neuropathic pain management: A promising therapy in need of optimization. International Anesthesia Research Society, 124(2), 661-674.
doi: 10.1213/ANE.0000000000001787
Niesters, M., Martini, C., Dahan, A. (2013). Ketamine for chronic pain: Risks and
benefits. British Journal of Clinical Pharmacology 77 (2), 357-367. doi:10.111/bcp.12094
Olson, J.C., Ogarek, J.L., Goldenberg, E.J., Sulo, S., (2016, December). Impact of a chronic pain protocol on emergency department utilization. Academic Emergency Medicine, 23, 424-432. doi:10.1111/acem.12942/pdf
Patil, S. & Anitescu, M. (2012). Efficacy of outpatient ketamine infusions in refractory chronic pain syndromes: A 5-year retrospective analysis. Pain Medicine, (13), 263-269. doi:10.1111/j.1526-4637.2012.01241.x
Peltoniemi, M., Hagelberg, N., Olkkola, K., Saari, T., (2016). Ketamine: A reviewof the clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clinical Pharmacokinetics, 55, 1059-1077. doi:10.1007/s40262-016-0383-6
Pickering, A., & McCabe, C., (2014). Prolonged ketamine infusion as a therapy for complex regional pain syndrome: Synergism with antagonism? British Journal of Clinical Pharmacology, 77 (2), 233-238. doi:10.1111/bcp.12157
Polomano, R., Buckenmaier, C., Kwon, K., Hanlon, A., Rupprecht, C., Goldberg, C.,
Gallagher, R., (2013). Acute pain and perioperative pain section. Pain Medicine,
14: 1088 – 1100. Retrieved from, https://academic.oup.com/painmedicine/article-abstract/14/71088/1805997
Schilder, J., Sigtermans, M., Schouton, A., Putter, H., Dahan, A., Noldus, L.,
Marinus, J., and vanHilten, J., (2013). Pain relief is associated with improvement in motor function in complex regional pain syndrome, type 1: Secondary analysis of a placebo-controlled study on the effects of ketamine. The Journal of Pain, 14 (11) 1514 – 1521, http://dx.doi.org/1016/j.pain.2013.07.2013
Tighe, P., Buckenmair, C., Boezaart, A., Carr, D., Herring, A., Mackey, S.,
Mariano, E., …Reisfield, G., (2015). Acute pain medicine in the United States: A
status report. Pain Medicine, 16, 1806 – 1826. doi:10.1111/pme12760
Xu, J., Yang, J., Lin, P., Rosenquist, E., & Cheng, J. (2016). Intravenous therapies for complex regional pain syndrome: A systematic review. Anesthesia & Analgesia 122 (3) 843-856. doi:10.1213/ANE.00000000000000999
Zhao, J., Wang, Y., Wang, D., (2018). The effect of ketamine infusions in the treatment complex regional pain syndrome: A systematic review and meta-analysis. Current Pain and Headache Report (22) 12, 1-8. https://doi.org/10.101007/s11916-018-0664

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