Correspondence / American Journal of Emergency Medicine 35 (2017) 914-932 917

Auras R. Atreya, MD Division of Cardiology, Department of Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

http://dx.doi.org/10.1016/j.ajem.2017.02.037

References

1. Riley RF, Miller CD, Russell GB, Harper EN, et al. cost analysis of the History, ECG, Age, Risk factors, and initial Troponin (HEART) Pathway randomized control trial. Am J Emerg Med 2017 Jan;35(1):77-81.
2. https://www.cdc.gov/nchs/data/ahcd/nhamcs_emergency/2013_ed_web_tables.pdf. Accessed 27th January 2017.
3. Evers S, Goossens M, de Vet H, van Tulder M, et al. Criteria list for assessment of meth- odological quality of economic evaluations: Consensus on Health Economic Criteria. Int J Technol Assess Health Care 2005 Spring;21(2):240-5.
4. Finison K, Mohlman M, Jones C, Pinette M, et al. Risk-adjustment methods for all- payer comparative performance reporting in Vermont. BMC Health Serv Res 2017 Jan 19;17(1):58.

   Cost savings and the HEART Pathway:

   

   The author responds

   We very much appreciate the correspondence regarding our re- cent article describing a retrospective cost analysis of the HEART Pathway in the context of the larger randomized trial describing its use in a US cohort. While we should always aspire to examining the larger societal vantage point for novel therapeutics and deci- sion aids, it is often beyond the scope of an initial study. This study was the first of its kind, limited to a single institution, and in- cluded a small number of patients. We agree that there are a multi- tude of possible unmeasured confounders (payer mix, level of physician training, etc.) that may impact the real world economic impact of the HEART Pathway. Your comments provide ample fod- der for a further study which is the heart of clinical investigation. A larger trial with an economic analysis conducted from a societal perspective that has adequate power to tease out confounding var- iables is certainly warranted.

   In terms of the length of follow-up in this study, 30 day outcomes are the standard for many similar studies, though we understand the possi- bility of excluding components of cost that may be affected by use of the HEART Pathway and fall outside the 30-day window. However, we are currently evaluating one year follow-up data and will hopefully be pre- senting that in a separate article in the future.

   In regards to the number of uninsured in our population, this percentage is relatively small compared to other similarly-sized urban safety net hospitals, but may be large compared to commu- nity hospitals in affluent areas. We recognize that this constricts the generalized applicability of our study.

   Robert F. Riley

   Division of Cardiology, University of Washington Medical Center, 1959 NE

   Pacific Street, Seattle, WA 98157, United States

   E-mail address: [email protected].

   17 February 2017

   http://dx.doi.org/10.1016/j.ajem.2017.02.038

   Low dose ketamine in the age of opioids

   The opioid epidemic has been a conundrum of historic proportions for the house of medicine imposing significant disruptions on emergen- cy medicine practice. Emergency physician influence on the opioid epi- demic may be quite limited [1,2]. Notwithstanding, our specialty is significantly affected and solutions must be sought. Indeed, emergency physicians find themselves caught between customer satisfaction sur- veys, hospital administration expectations, Joint Commission trends and other external forces with respect to chronic pain management. Nu- merous alternative approaches to pain management for the opiate tol- erant patient presenting with pain to the emergency department have emerged over recent years but there is no consensus on a most effective strategy. In fact, there is nothing but diversity with approaches ranging from “Dilaudid-Free” emergency departments to nurse-driven proto- cols utilizing high dose hydromorphone for pain control for the same or similar patients.

   

   Sundry variables complicate the dilemma. The emergency de- partment patient population is one of the most diverse in medicine. Emergency physicians must address acute pain conditions and chronic nonmalignant pain syndromes typically within a single shift with discrimination variables often necessarily subjective. Fur- ther, there is little consensus even within individual groups; emer- gency physician opioid prescribing habits vary significantly even within in a single practice [3]. Emergency physicians reside in a “goldfish bowl” where physician medical decisions are subject to ex- ternal forces which may not coincide with best practice. Any mono- lithic approach or protocol driven application to our diverse patient population presenting with acute or chronic versus chronic pain is likely to be insufficient.

   The authors of the article in this issue of AJEM, “Low Dose Ketamine

   Use in the ED: A New Direction in Pain Management,” provide a timely review of an adjunctive approach to acute exacerbation of chronic pain and acute pain management. low-dose ketamine (LDK) has not yet reached the stage of widespread acceptance or utilization but it is “ready for prime time” consideration. LDK is another “arrow in the quiv- er” for pain management for selected ED patients, particularly for pa- tients opioid tolerant or dependent.

   Pourmand et al. do raise several important issues to be consid- ered for integration of LDK into our everyday practice. First, patient safety is paramount. The relevant literature supports the safety of ketamine at sub-dissociative doses, as detailed in the review. Nurs- ing protocols for managing and monitoring patients receiving LDK have been successfully and safely implemented in some institu- tions [4]. As emergency nursing practice varies by department, hospital-specific protocols are desirable. Adequate monitoring of patients receiving LDK with or without opioids is essential. Histor- ically, controversy regarding ketamine’s use in the emergency de- partment has occurred but political issues have largely been surmounted [5,6].

   Of course, emergency physicians are loathe to advocate another drug to mediate opioid over-use in the emergency department that has sim- ilar abuse potential. Ketamine is not a common drug of abuse in the United States compared with opioids [7]. However, Ketamine abuse is a significant problem internationally, particularly in China and South- east Asia, where it is frequently cited within the top three most com- monly used illicit drugs [8,9]. When used recreationally, ketamine is most often procured as a powder obtained from pharmaceutical sources (i.e., veterinary or medical stock), large-scale international drug traffick- ing, and various internet suppliers [10]. Though the exact mechanisms of addiction are poorly-defined for ketamine, the drug clearly demon- strates reinforcing properties and the risks for misuse, addiction, and di- version which must be considered, However, there is nothing to suggest that the emergency department prescription of ketamine is associated with an increased incidence of subsequent abuse.

   918 Correspondence / American Journal of Emergency Medicine 35 (2017) 914-932

   Ketamine’s general safety and appropriate prescription by emergen- cy physicians, as well as, its Acute therapeutic use in the emergency de- partment administration are no longer issues of debate and medical politics. On a scientific basic, LDK should face less controversial integra- tion as an adjunctive therapy integrated into the management of acute and chronic pain in the emergency department.

   Richard M. Sobel, MD, MPH

   Southern Regional Medical Center, Riverdale, GA,

   United States

   Corresponding author:

   E-mail address: [email protected]

   Alaina R. Steck, MD

   Department of Emergency Medicine, Emory University, Atlanta, GA,

   United States

   http://dx.doi.org/10.1016/j.ajem.2017.03.062

   References

   Levy B, Paulozzi L, Mack KA, Jones CM. Trends in opioid Analgesic prescribing rates by specialty, U.S., 2007-2012. Am J Prev Med 2015;49(3):409-13.

5. Ringwalt C, et al. Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses. Pain Res Manag 2014;19(4):179-85.
6. Barnett ML, Olenski AR, Jena AB. Opioid-prescribing patterns of emergency physi- cians and risk of long-term use. N Engl J Med 2017;376(7):663-73.
7. Sobel RM. Emergency physician ketamine administration complies with JCAHO reg- ulation. J Emerg Med 2001;19(1):91.
8. Sobel RM, Morgan BW. Ketamine in the emergency department: medical politics vs. patient care. Am J Emerg Med 1999;17(7):722-5.
9. Porter SB, et al. Perioperative ketamine for post-operative analgesia: the Mayo Clinic-Florida experience. J Perianesth Nurs 2015;30(3):189-95.
10. Palamar JJ, et al. Self-reported use of novel psychoactive substances among at-

    tendees of electronic dance music venues. Am J Drug Alcohol Abuse 2016;42(6): 624-32.

    Chen WJ, et al. Ketamine use among regular tobacco and alcohol users as revealed by respondent driven sampling in Taipei: prevalence, expectancy, and users’ risky deci- sion making. J Food Drug Anal 2013;21(4):S102-5.

11. Sassano-Higgins S, et al. A review of ketamine abuse and diversion. Depress Anxiety 2016;33:718-27.
12. Liu Y, Lin D, Wu B, Zhou W. Ketamine abuse potential and use disorder. Brain Res Bull 2016;126:68-73.

    Low dose ketamine use in the emergency department, a new direction in pain management

    

    Introduction

    The US is amidst of an epidemic of Opioid misuse, abuse, and diver- sion [1-3]. In the past decade, a 300% increase in opioid analgesic pre- scribing has been accompanied by a three-fold increase in drug overdose deaths and a two-fold increase in emergency departments (ED) visits for opioid misuse and abuse [4,5]. Opioid analgesics are com- monly administered and prescribed from the ED; however, the ED’s contribution to the current epidemic remains unclear [6]. In addition, patients are commonly treated with opioid analgesics for a variety of conditions in the outpatient setting and may be tolerant, making pain management in the ED more challenging. The use of high doses of opi- oid analgesics has been associated with life-threatening adverse effects, secondary to respiratory depression [7,8]. In an effort to curb opioid misuse and abuse, as well as to promote safe and rational opioid pre- scribing, there has been a renewed interest in alternative non-opioid analgesics.

    Low dose ketamine (LDK) has emerged as a safe and effective Non-opioid alternative for patients with chronic or refractory as well as acute pain. Ketamine is a distinct pharmacologic agent with a unique mechanism of action and Adverse effect profile. It is not sim- ply an “opioid substitute”. LDK can be used in the ED in a variety of clinical situations. It can be used for patients who neED analgesia prior to an awake procedure. LDK can also be used in the setting of an acute exacerbation of pain in patients that are at high-risk of ad- verse effects from opioids and when other non-opioid therapies (such as Non-steroidal anti-inflammatory drugs) have failed. Keta- mine may also be useful to treat acute pain in the setting of hemody- namic instability [9]. Some particularly challenging groups are patients presenting with acute exacerbations of nonmalignant chronic painful conditions such as Sickle cell anemia [10], dento- facial pain syndromes [11], headaches [12], axial skeletal pain [13, 14], and gastroparesis. Patients with malignant and non-malignant chronic pain are often on high-dose opioid analgesics at baseline, making their pain difficult to manage in the ED. ketamine infusion may be of utility in opioid-tolerant patients with acute intractable exacerbations of chronic pain by a proposed mechanism of re- sensitizing to their opioid regimen [15]. In recent years, there has been a renewed interest in and study of ketamine in the ED. This re- view will focus on the use of LDK for the acute treatment of pain, with a focus on its utilization in the ED setting.

    Ketamine mechanism of action and pharmacokinetics

    Ketamine is a well-known N-methyl-D-aspartate (NMDA) recep- tor antagonist. One of the normal functions of the NMDA receptor is to potentiate painful stimuli, which may lead to a “hyperalgesia” or “central sensitization”. Ketamine’s analgesic effect has been attrib- uted, in part, to its ability to block this sensitization [16]. Ketamine is a non-competitive NMDA receptor antagonist with a, “slow off rate” causing a prolonged tonic blockade of the receptor contribut- ing to long lasting Analgesic effects [17]. Ketamine also has direct effects on the delta opioid receptor and acts to augment opioid mu-receptor function [17]. The way by which ketamine augments opioid receptor function has been attributed to downstream effects involving the extracellular signal-regulated kinase 1/2 (ERK1/2). Ketamine potentiates opioid induced ERK1/2 phosphorylation, re- quiring lower opioid doses for equal phosphorylation [18]. Keta- mine has also been shown to delay desensitization and improve re-sensitization of Opioid receptors resulting in prolonged overall effect of opioid stimulation, which may be useful in patients with opioid-related hyperalgesia [18].

    Ketamine has a high first pass metabolism. The oral availability is between 17 and 24% for racemic ketamine and 8-11% for S- ketamine [19]. Intramuscular bioavailability is 90-93%. Ketamine is initially distributed to highly perfused tissues such as the brain, lungs, and heart where it can reach up to 5 times plasma concentra- tions [20]. Ketamine is metabolized by CYP3A and CYP2B6 through N-demethylation to norketamine, which has about one-third of the activity of ketamine [19,20]. The only absolute contraindication to ketamine is for patients who have an allergy to ketamine. Rela- tive contraindications include: moderate to Severe hypertension, congestive heart failure, pregnancy, or acute alcohol intoxication [20]. Traditionally, there has been a theoretical concern that keta- mine can cause increased intracranial pressure, but recent studies have demonstrated ketamine does not significantly increase intra- cranial pressure [21,22,23]. Ketamine use has been reported to result in an emergence delirium or emergence reaction. This phe- nomenon includes alterations in mood and body image, dissociative experiences, vivid dreams and illusions, and delirium. This reaction may be more frequent with larger doses of ketamine, in patients older than 16 years of age, and in female patients [24].