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Perioperative ketamine as a strategy to decrease opioid use in anesthesia care for opioid dependent patients with chronic pain: an extensive literature review with practice recommendations

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Perioperative ketamine as a strategy to decrease opioid use in anesthesia care for opioid dependent patients with chronic pain: an extensive literature review with practice recommendations

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Content PERIOPERATIVE KETAMINE TO DECREASE OPIOID USE

PERIOPERATIVE KETAMINE AS A STRATEGY TO DECREASE OPIOID USE IN
ANESTHESIA CARE FOR OPIOID DEPENDENT PATIENTS WITH CHRONIC PAIN: AN
EXTENSIVE LITERATURE REVIEW WITH PRACTICE RECOMMENDATIONS
by
Touraj Sedigh

A Doctoral Capstone Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the Requirements for the Degree
DOCTOR OF NURSE ANESTHESIA PRACTICE

May 2021

ii

The following manuscript was contributed to in equal parts by Emily Marsh and Touraj Sedigh.

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Dedication
For all of the anesthesia providers who work to achieve best-in-class patient care and who
demonstrate an honest commitment to personal and professional growth and improvement.

iv

Acknowledgments
This paper would not have been possible without the instruction and support from the
faculty of the Doctorate Nurse Anesthesia Program at the University of Southern California. We
have benefited greatly from the mentoring of our capstone faculty chair, Dr. Charles Griffis. He
displays a tremendous desire to learn and understand anesthetic management to further our
profession. We are truly indebted to him for fostering the same pursuit and fascination in us and
of course, for his assistance and advice during our years as his student.

v

Table of Contents
Dedication ...................................................................................................................................... iii

Acknowledgments ..................................................................................................................................... iv

List of Tables ............................................................................................................................................. vi

Abstract ..................................................................................................................................................... vii

Chapter 1 ..................................................................................................................................................... 1
Introduction ............................................................................................................................................. 1
Clinical Problem/Issue and Specific Aims .......................................................................................... 2
Background and Significance ............................................................................................................... 3

Chapter 2 ..................................................................................................................................................... 8
Methodology ........................................................................................................................................... 8

Chapter 3 ................................................................................................................................................... 10
Literature Review ................................................................................................................................. 10

Chapter 4 ................................................................................................................................................... 16
Results .................................................................................................................................................... 16
Recommendations for Practice ........................................................................................................... 16

Chapter 5 ................................................................................................................................................... 18
Discussion ............................................................................................................................................. 18
Conclusion ............................................................................................................................................. 20

References ................................................................................................................................................. 22

Appendix ................................................................................................................................................... 29
Appendix A ........................................................................................................................................... 29

vi

List of Tables
Table 1 ........................................................................................................................................... 8

vii

Abstract
The United States is facing an opioid overdose epidemic, affecting the pain management
practice of health care providers. Current literature provides multiple options for anesthesia
providers to change the practice of using opioids in pain treatment. Multimodal analgesia
improves perioperative pain control and decreases opioid use and ketamine, a non-competitive
N-methyl-D-aspartate (NMDA) receptor antagonist, may be used. Although the literature is rich
in studies about ketamine, the large number of ketamine studies challenges healthcare providers
to find appropriate practice recommendations. An extensive literature review was conducted to
identify the safest and most effective method of using ketamine to provide analgesia during
anesthesia care for opioid-dependent patients with chronic pain. The literature revealed a
significant reduction in opioid consumption and decreased levels of pain in opioid-dependent
patients with chronic pain who received ketamine. Optimally, ketamine infusion should be
started intraoperatively and continued during the first 24 hours postoperative period, with an
appropriate level of postoperative monitoring. Otherwise, the ketamine infusion should be
continued until the end of the surgery for maximum efficacy and to ensure the safety of the
patient. The most acceptable dosage is a 0.5 mg/kg bolus followed by 0.5-0.6 mg/kg per hour
infusion until the end of the surgery. Postoperatively, the infusion rate might be decreased to
0.12-0.2 mg/kg per hour. Ketamine infusion may be beneficial in reducing postoperative opioid
consumption in opioid dependent patients and should be added to the pain treatment regimen
unless medically contraindicated.
Key words: Opioid epidemic, perioperative medicine, multimodal analgesia, non-opioid
analgesics, ketamine, opioid-free pain management
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Chapter 1
Introduction
Opioid misuse, overdose, dependence and addiction comprise a concerning epidemic,
affecting a considerable number of patients, their families and the pain management practices of
health care providers (Phillips et al., 2017). The adoption of prescription opioids as the golden
standard for pain treatment developed in the 1990s; twenty years later, opioid overdose is a
leading cause of death (National Safety Council, 2017). This problem is particularly striking in
the acute perioperative pain management of patients with chronic pain syndromes treated with
opioid drugs (Tan et al., 2018). A reshaping of the pain treatment delivery system is taking place
and anesthesia providers take a leading role in influencing the perioperative treatment of
patients’ pain, including those with chronic pain syndromes (Jackman, 2019). Current literature
provides various opinions on options for anesthesia providers to change their practices regarding
the use of opioids in pain treatment, by introducing different ways to manage a patient’s pain
(Koepke et al., 2019). A promising current topic is the perioperative use of ketamine (Schwenk
et al., 2018). Although the literature is rich in studies about ketamine, the rapidly increasing
number of ketamine studies is extremely challenging for the average healthcare provider to
navigate in an attempt to find straight forward practice recommendations (Hisham et al., 2016;
Love, 2013; Mccoll et al., 1998).
The research question guiding this project can be stated as, “What is the safest, most
effective and efficacious method of using ketamine to provide analgesia during anesthesia care
for patients who are opioid-dependent and have chronic pain?” The
Population/Intervention/Outcome (PIO) question guiding this project can be stated as follows.
The population (P) is patients with the dual comorbidities of chronic pain and opioid
2

dependence, explored by the intervention (I) of reviewing articles discussing ketamine as a
strategy to decrease opioid use during the perioperative period for these patients. This may
include both patients with opioid use disorder (OUD---an addictive disease characterized by
drug-seeking behaviors, escalating and hazardous use of opioids, etc.) as well as patients who are
not addicted, but have chronic pain and are on chronic opioid therapy without addiction
behaviors. The outcome (O) is to analyze this literature and identify best practice
recommendations for ketamine use during the perioperative period for this specific patient
population.
Clinical Problem/Issue and Specific Aims
The clinical problem has two parts. The first part is the challenge in the provision of
adequate, safe analgesia for this population, in which patients may be tolerant to opioids and may
have opioid-induced hyperalgesia and allodynia (Tan et al., 2018). These specific characteristics
make managing their analgesic needs uniquely difficult and are more fully described in the next
section. Patients with opioid dependence and chronic pain have become increasingly common to
see in clinical practice and a large volume of literature has arisen to provide clinical providers
with recommendations for evidence-based practice for this specific patient population (Dowell et
al., 2016; Schwenk et al., 2018).
The second part of the clinical problem for providers is evaluating the vast amount of
literature on this topic and choosing the best practices. Ketamine as an option for pain
management for opioid-tolerant patients with chronic pain is only a subset of the literature, but
searching PubMed with the phrases “opioid use disorder” and “analgesia” yielded over 500
results. Many of these articles do not focus their aims on criteria that are directly applicable to
patient care in clinical practice. Furthermore, the average healthcare provider is challenged with
3

finding enough time to sift through the multitude of articles on this topic, to cross-reference and
find practice recommendations while simultaneously caring for patients in the field (Hisham et
al., 2016). Therefore, the second part of the problem is the lack of a concise summary of
literature in the care for these patients.
Considering these two clinical problems and their relationship with one another, the aim
of this project is to distill the literature based on specific criteria in the care for these patients and
consequently, to provide a single comprehensive set of recommendations. The specific criteria
this project uses in recommending best practices for ketamine use are safety, effectiveness and
efficacy. Safety is operationally defined as the condition of being free from harm or risk; or
affording safety or security from danger and risk . Effectiveness is the ability to produce a
decided, decisive, or desired effect. Efficacy is the ease with which the provider is able to
produce the desired effect.
Background and Significance
The United States is facing an opioid overdose epidemic, which affects an increasing
number of patients each year (Rudd et al., 2016). Between 2000 and 2014, there has been a
200% increase in the rate of overdose deaths involving opioids (Rudd et al., 2016). In 2014
alone, 60.9% of 47,055 drug overdose deaths were related to opioid use (Rudd et al., 2016).
Although opioids have always been part of pain control regimens for the patients, the new trend
of the extensive use of opioids started on the 1990s, when the pain was recognized as the 5th
vital sign and physicians were told that the risk of addiction was low when opioids were
prescribed for chronic pain U.S. (Alam & Juurlink, 2016; Leung et al., 2017). Prior to this, the
prescription of opioids was limited to cancer patients and doctors were hesitant to prescribe
opioids for non-cancer patients. In January 1980, Jane Porter and Hershel Jick, of the Boston
4

Collaborative Drug Surveillance Program at Boston University Medical Center, published a
letter in the New England Journal of Medicine (Porter & Jick, 1980). In the letter, it was
reported that among 11,882 patients who received at least one narcotic medication, in patients
who had no history of addiction, only four cases of well-documented addiction were reported.
Based on this simple observational study, researchers concluded the development of dependence
is rare in medical patients with no history of addiction (Porter & Jick, 1980). Not only are causal
inferences incorrect when based on observation, but this study was also conducted during a time
of sparse and restricted opioid use. Therefore, drawing these conclusions was questionable at
best.
Moving forward, the uncritical and inaccurate citation of this original letter was a major
contributing factor in creating the opioid misuse crisis in the U.S. Leung et al. (2017) examined
the medical literature and found that the 1980 letter had been cited 608 times, far more often than
similar letters published in the journal around the same time. The authors noted inaccurate
citation as 81% of the articles failed to note that the patients were in the hospital at the time they
received the prescription and 75% of the articles cited the letter as proof that addiction was
uncommon in patients treated with opioids.
Furthermore, a marked increase in the number of citations was noted, after OxyContin®,
a long-acting formulation of oxycodone was introduced into the market in 1995 (Leung et al.,
2017). In 2001, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)
recognized early recognition and management of pain as a standard of care (Alam, & Juurlink,
2016). Guidelines recommending relaxed prescription of opioids for multiple indications
emerged from different medical societies, and pharmaceutical companies supported this growing
trend and utilized aggressive and sometimes deceptive marketing strategies for new opioid
5

formulations (Alam, & Juurlink, 2015). In 2007, the manufacturer of OxyContin®, Purdue
Pharma, L. P., pleaded guilty that they misled the public about the risk of addiction associated
with the drug (Leung et al., 2017). It has been speculated that this inappropriate use of poorly
evaluated studies and aggressive and dishonest marketing strategies led to the over-prescription
and misuse of opioids and is linked to the current opioid crisis in the United States (Leung et al.,
2017).
Addressing the current opioid crisis requires a multidimensional, collaborative approach.
Healthcare providers in particular, play a vital role in this multidimensional approach due to their
prescription privileges and education capacities that might alter the behavior of opioid users.
Pain after surgery is a common postoperative complaint and on a survey by Warfield and Kahn
(1995), 77 percent of adult patients reported pain after surgery, with 80 percent of those
experiencing moderate to extreme pain. In the survey of 300 patients, Gan et al. (2014) reported
comparative results, with 86 percent of the patients experiencing pain after surgery; and of these,
75 percent had moderate/extreme pain during the immediate post-surgical period.
The use of opioids to control the postoperative pain for hospitalized patients is a common
practice, which began in the 1800s, with the discovery of morphine (Sabatowski et al., 2004).
The efficacy of opioid analgesia was very appealing in the management of perioperative pain,
though use was restrained prior to the 1990s due to fears of addiction, as previously discussed
(Leung et al., 2017). In the 1990s, opioid use began to increase rapidly and in a retrospective
study by Kessler et al. (2013), of 37,031 patients aged 18 years or older, 98.6 percent received
postsurgical opioids and 57.3 percent of these patients received a combination of parenteral and
oral medications. In a retrospective study of over 36,000 opioid-naïve patients who had surgery,
Brummett et al. (2017) noted the incidence of chronic opioid use after surgery was 5.9% to 6.5%.
6

With the new evidence showing a link between acute exposure to opioids and chronic opioid
dependence and considering a significant amount of opioid use happens during the perioperative
period, anesthesia providers have an important role in optimizing the utilization of opioids.
Regardless of the analgesic regimen used, appropriate postoperative pain control is
crucial as patients with inadequate postoperative pain control are at increased risk of
cardiopulmonary and other complications (Shea et al., 2002). The authors noticed higher
postoperative pain scores after abdominal surgery on the patients who developed postoperative
pulmonary complications (PPC) and identified pain as a factor that contributes to the
development of PPC. The patients with a PPC got up to a chair and walked fewer times per day
on postoperative days one to six than those without. Immobility is a known risk factor for the
development of deep venous thrombosis (Braun & Kassop, 2019) and this is a contributing factor
to developing pulmonary complications on these patients. Appropriate postoperative pain
control will lead to faster recovery, improved mobility, reduced complications and improved
patient satisfaction (Kurd et al., 2017).
Multimodal analgesia is one strategy to improve perioperative pain control and decrease
opioid use after the surgery (Rosero & Joshi, 2014). It consists of the administration of two or
more medications which target different pain receptors and pathways and provides analgesia
through different mechanisms. The aim is to develop a synergistic effect and improve pain relief
while reducing opioid requirements. A multimodal analgesia protocol should be individualized
based on the patient's characteristics and the type of the surgery. Components of this protocol
may include opioids, non-opioid systemic analgesics like acetaminophen, non-steroidal anti-
inflammatory drugs, gabapentinoids, ketamine and local anesthetics (Schwenk & Mariano,
2018).
7

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, is one
of the useful options often included in multimodal analgesia, as activation of central nervous
system NMDA receptors is one of the proposed mechanisms for the development of tolerance
and delayed hyperalgesia (Maher et al., 2017). Ketamine is a phencyclidine derivative known
initially as CI-581, first synthesized in the early 1960s as an anesthetic agent with unique
properties including minimal adverse effects on the cardiorespiratory system (Gorlin et al.,
2016). As an anesthetic agent, ketamine can be used to induce anesthesia, sedation, analgesia
and amnesia. Patients receiving ketamine often maintain functional residual capacity and
experience bronchodilation while avoiding cardiovascular depression (Haas & Harper, 1992).
Since the 1980s, investigations have revealed a critical role of the NMDA receptor in
pain processing, and this has produced renewed interest in ketamine as an analgesic (Chizh,
2007) and the use of ketamine in subanesthetic concentrations for analgesia has sharply
increased in recent years. The efficacy of ketamine in chronic pain likely involves reversing
central sensitization and enhancing descending modulatory pathways (Niesters et al., 2014). The
analgesic effect of ketamine in acute pain is secondary to its non-reversible antagonism of the
NMDA receptor, although it also has an effect on [mu]-opioid receptors, muscarinic receptors,
monoaminergic receptors and [gamma]-aminobutyric acid receptors (Maher et al., 2017).

8

Chapter 2
Methodology
An extensive literature review was conducted utilizing PubMed (a free database
developed and maintained by National Center for Biotechnology Information, website:
https://www.nlm.nih.gov) and Web of Science (a website which provides subscription-based
access to multiple databases that provide comprehensive citation data for many different
academic disciplines, originally produced by the Institute for Scientific Information and is
currently maintained by Clarivate Analytics, website: https://www.webofknowledge.com) search
engines via Norris Medical Library. Search terms used for the different sections included but
were not limited to: “opioid epidemic”, “nurse anesthetist”, “anesthesiologist”, “perioperative
medicine”, “safety”, “efficacy”, “effectiveness”, “multimodal analgesia”, non-opioid
analgesics”, “opioid”, “opioid-use disorder”, “ketamine”, “N-methyl-D-aspartate receptor”,
“subanesthetic” and “opioid-free pain management”. The bibliographic entries for each article
were examined. The snowballing technique was implemented to find related articles. The
inclusion and exclusion criteria of articles returned from the search are outlined in Table 1.

The articles meeting the criteria to be included in the literature review were evaluated for
accuracy and reliability and then the articles were analyzed to identify recent recommendations
Table 1
Inclusion Criteria
· English language
· Peer-reviewed and after 2008
· Patients requiring anesthesia for surgical procedures
· Perioperative analgesia
· Perioperative analgesia for patients with chronic pain
· Perioperative analgesia for patients with opioid dependency
Exclusion Criteria
· Non opioid-dependent patients
· Patients who do not require pre, intra and post-operative care.
9

for most effective, efficacious and safest methods of ketamine administration to decrease opioid
use during anesthesia. A total of 14 articles met the inclusion and exclusion criteria and were
included in the final literature review for critical analysis and to identify recent practice
recommendation. A literature chart of all the studies reviewed to select final 14 articles is shown
in Appendix A.

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Chapter 3
Literature Review
In the opioid-dependent patients, central sensitization mechanisms involving NMDA
receptors are activated (Barreveld et al., 2013). Thus, ketamine with a pharmacologic action of
non-competitive NMDA receptor antagonism, could potentially be a particularly useful option to
reduce opioid consumption and pain intensity throughout the postoperative period in these
patients in whom pain may be difficult to manage with opioids alone (Koepke et. al, 2018).
Patients who receive opioids on a chronic basis to control pain in the acute perioperative
period usually require increased doses to maintain the same analgesic effects. The increased
requirement is attributed to both the development of tolerance to the analgesic effects of
chronically-administered opioids and opioid-induced hyperalgesia (Chu et al., 2008). Tolerance
occurs when the patients require higher than usual doses of the opioid to achieve the desired
analgesic effect. Tolerance is most likely due to receptor desensitization and increased synthesis
of cAMP (Chu et al., 2008). Hyperalgesia and tolerance are different phenomena that can result
in similar increases in opioid requirements (Chu et al., 2008).
Opioid-induced hyperalgesia is defined as nociceptive sensitization caused by exposure
to opioids (Chu et al., 2008). This phenomenon is characterized by a paradoxical response as a
patient receiving opioids for the treatment of pain may become more sensitive to painful stimuli.
Although the precise molecular mechanism is unclear, it is assumed to result from neuroplastic
changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive
pathways (Chu et al., 2008). Some of the proposed mechanisms include extensive internalization
and inactivation of mu-opioid receptors, opioid-induced up-regulation of cyclic adenosine
monophosphate pathway and activation of central NMDA nociceptive systems (Joly et al.,
2005).
11

In a prospective, double-blinded study by Loftus et al. (2010), opioid-dependent patients
undergoing major lumbar spine surgery were randomized to receive ketamine bolus on induction
(0.5 mg/kg) and continuous infusion (10 μg/kg/min) until wound closure, or saline of equivalent
volume and were observed for 48 hours postoperatively to evaluate morphine consumption. The
study demonstrated that the patients who received ketamine during the surgery consumed 37%
less morphine on average during the 48-hour postoperative period. Furthermore, the patients in
the treatment group reported a 26.7% reduction in pain intensity in the post-anesthesia care unit
(PACU) and a 26.2% reduction in pain intensity at their first follow-up visit at six weeks.
Moreover, the doses of ketamine used in this study demonstrated an acceptable safety profile and
the authors noted ketamine was not associated with a significant change in blood pressure heart
rate from baseline values during the intraoperative, PACU, or hospital ward periods.
Urban et al. (2008) evaluated the use of ketamine as an adjunct to acute pain management
in opioid-dependent patients after spinal fusion surgery. Patients with a history of narcotic
ingestion on a regular schedule daily (> 60 mg equivalent oxycodone) were included in the
study. The study did not specify the duration of chronic narcotic use for the patients included in
the study. A total of 26 patients scheduled for one or two-level posterior lumbar fusion with
segmental instrumentation surgery were randomly assigned to receive ketamine or act as a
control. All the patients received subarachnoid morphine (10 mcg/kg) at instrumentation and the
patients in the ketamine group received 0.2 mg/kg ketamine IV on induction and then 2
μg/kg/hour as a continuous IV infusion until discharge from the PACU. Patients in the ketamine
group had significantly less pain during their first postoperative hour in the PACU and continued
to have less pain during the first postoperative day at rest and with physical therapy. The authors
noted patients in the ketamine group required less hydromorphone than the control group, but the
12

differences were not significant, which could be attributed to the small number of patients
enrolled in the study. Both groups had similar levels of sedation and nausea and vomiting.
Psychotomimetic effects seen with anesthetic doses of ketamine were not reported in this study,
although the study was not designed or powered to detect these effects of ketamine.
Barreveld et al. (2013) evaluated 64 patients with chronic pain taking opioids undergoing
non-oncologic surgery. Patients were randomized to receive either postoperative
hydromorphone patient-controlled analgesia (PCA) and continuous ketamine infusion (0.2
mg/kg/hour), or hydromorphone PCA and saline. The authors observed a significant reduction
in “average” pain scores in the ketamine group vs. placebo and no difference in “least” and
“worst” pain scores. Also, no reduction in overall postoperative opioid consumption was noted.
Administering a ketamine infusion at 0.2 mg/kg/hour was not associated with adverse
hemodynamic changes or with noticeable cognitive-behavioral changes.
In another more recent study, in a randomized, double-blind clinical trial, Nielsen et al.
(2017) evaluated the effect of intraoperative ketamine on immediate postoperative opioid
consumption in chronic pain patients with opioid dependency undergoing lumbar spinal fusion
surgery. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus
0.5 mg/kg and infusion 0.25 mg/kg/hour or placebo. The authors noted that ketamine was
effective in decreasing opioid use and morphine consumption via intravenous patient-controlled
analgesia pump (PCA) 0 to 24 hours postoperatively was significantly reduced in the ketamine
group compared with the placebo group. Furthermore, the authors did not observe any
significant difference regarding nausea, vomiting, hallucinations, or nightmares between the two
groups.
13

Zakine et al. (2008) compared the effects of intraoperative IV ketamine administration
alone versus combined intraoperative and postoperative administration to evaluate the effect of
duration of ketamine administration as an independent factor in reducing postoperative pain. In
a double-blind, randomized clinical trial of patients undergoing abdominal surgery, investigators
compared the difference on postoperative opioid consumption, pain reduction and side effects
when ketamine administration was restricted to the intraoperative period or continued for 48
hours postoperatively. The patients were divided into three groups: Group 1 received ketamine
intraoperatively and for the first 48 hours post-surgery (2 μg/kg/min after a 0.5 mg/kg bolus);
group 2 received intraoperative ketamine administration only (2 μg/kg/min after a 0.5 mg/kg
bolus); and group 3 received placebo. The authors observed significantly lower cumulative
morphine consumption 24 hours after surgery in patients who continued to receive ketamine
postoperatively. Moreover, compared to the control group, the incidence of nausea and vomiting
was significantly lower on patients who continued to receive ketamine postoperatively and the
authors did not observe any psychiatric disorders, delusions, nightmares, or other sleep disorders.
The unique pharmacology of ketamine may be helpful in the opioid-dependent
perioperative patient population for more than analgesic efficacy. Opioid-dependent patients are
particularly at risk for perioperative depressive symptoms (PDS) as they frequently have
depression as a co-diagnosis (Davis et al., 2017). A study from 2017 showed that 19% of the
28.6 million Americans with mood disorders use prescription opioids, compared to 5% of the
general population. Furthermore, the analysis showed that adults with mood disorders receive
51% of the opioid prescriptions distributed in the US (Davis et al., 2017). Perioperative
depressive symptoms represent a common perioperative complication; depression symptoms
14

have a negative effect on mental health and lead to poor clinical outcomes (Moussavi et al.,
2007).
Furthermore, PDS increases the incidence of postoperative delirium (Inouye, 2006). A
common stigma attached to the use of ketamine in regards to safety is the risk of negative
psychiatric symptoms, such as delirium and depression, yet this drug is now increasingly being
researched for its efficacy in the treatment of depression (Hu et al., 2016). Several investigations
have used the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton
Depression Rating Scale, to establish that ketamine has a rapid antidepressant effect in
examining a population of patients with treatment-resistant depression (Kishimoto et al., 2016;
Singh et al., 2016). In one study, ketamine (0.5 mg/kg per body weight) was administered twice
weekly for two weeks and the improvement in the depression response rate was as high as 69%
(Singh et al., 2016). In another, fourteen studies enrolling 588 patients were reviewed and the
same dose of ketamine was found to significantly improve depression for seven days (Kishimoto
et al., 2016).
Although many recent studies focus on the overall benefits of ketamine to decrease PDS
risk - both prophylactically before surgery and upon discharge, a new study emerged in Beijing
Tiantan Hospital to discover its use intraoperatively (Zhou et al., 2018). A single-center,
randomized, placebo-controlled, double-blind trial aimed to find if low-dose ketamine relieved
PDS in patients undergoing supratentorial brain tumor resection (Zhou et al., 2018). Patients
were divided into ketamine and placebo groups. The ketamine group received 0.5 mg/kg per
body weight for a 40-minute infusion upon dural opening, while the placebo group received
normal saline at the same infusion rate. The chief anesthesiologist was blinded to the grouping
to allow for a double-blind trial and all patients received the same induction, maintenance and
15

emergence anesthetic medications. The MADRS score was used pre and postoperatively to
assess the presence of depression by trained and qualified doctors. The research is ongoing, but
preliminary data from the study has since reported a significant decrease in MADRS score
(meaning depression symptoms improved) during the 7-10 day postoperative period for the non-
placebo group, using postoperative three days as the primary point for data. Furthermore,
psychiatric symptoms and somatization disappeared two hours after the ketamine infusion was
stopped.

16

Chapter 4
Results
Based upon this extensive review of the literature, the following recommendations
regarding ketamine to decrease opioid use in anesthesia care for opioid dependent patients with
chronic pain are provided. Ketamine infusion should be considered for all opioid-dependent
patients. The benefit of subanesthetic low doses of ketamine for these patients are illustrated by
objective measures such as reduced opioid consumption and improved pain score in the
postoperative period. With diligent patient monitoring by properly trained providers, ketamine
can be used safely on this patient population.

Recommendations for Practice
1. Consider the addition of ketamine infusion to the treatment regimen of all opioid-dependent
with patients with chronic pain undergoing a surgical procedure unless medically
contraindicated (Barreveld et al., 2013; Loftus et al., 2010; Nielsen et al., 2017; Urban et al.,
2008; Zakine et al., 2008).
2. Consider the anti-depressive benefits of ketamine for opioid-dependent patients who have a
co-diagnosis of depression (Kishimoto et al., 2016; Singh et al., 2016)
3. Ketamine infusion should be started intraoperatively and to be continued during the first 24
hours postoperative period, with the caveat that an appropriate level of postoperative
monitoring is available. Otherwise, continue the ketamine infusion until the end of the
surgery for maximum efficacy and to ensure the safety of the patient (Urban et al., 2008;
Zakine et al., 2008).
17

4. The recommended dose of ketamine for opioid-dependent patients as a component of
multimodal analgesia: 0.5 mg/kg bolus followed by 0.5-0.6 mg/kg per hour infusion until the
end of the surgery. If the infusion is continued during the postoperative period, consider
decreasing the infusion rate to 0.12-0.2 mg/kg per hour (Barreveld et al., 2013; Loftus et al.,
2010; Nielsen et al., 2017; Urban et al., 2008; Zakine et al., 2008).

18

Chapter 5
Discussion
The benefit of intraoperative ketamine in pain control and decreasing opioid requirement
is likely due to a combination of a reduction in central sensitization via NMDA receptor
antagonism, reduction in opiate tolerance and some impact on the balance of neurotransmitters
(Loftus et al., 2010). In the literature review, a significant reduction in opioid consumption was
observed, in addition to the decreased level of pain in opioid-dependent patients with chronic
pain who received ketamine (Loftus et al., 2010; Nielsen et al., 2017). However, in the
investigations by Urban et al. (2008) and Barreveld et al. (2013), the patients who received
ketamine had a significant decrease in pain level but the reduction in postoperative opioid
consumption was not significant. Notably, in Barreveld et al. (2013), ketamine administration
was limited to the postoperative period and the study demonstrated improved average pain scores
but no significant difference in opioid use. Based on these findings, it appears that the addition
of ketamine infusion to the treatment regimen of these opioid-dependent patients may have been
beneficial in the context of this study. It can be speculated, pending more research, that
ketamine infusion may be beneficial in reducing postoperative opioid consumption in opioid
dependent patients, unless medically contraindicated.
Moreover, the additional benefit of continuous use of ketamine during both intraoperative
period and postoperative period compared to intraoperative only was also noted in the
investigation by Zakine et al. (2008). Based on these findings, we observed that when ketamine
infusion is started intraoperatively and continued during the first 24 hours postoperative period,
analgesia appears to be improved. An important pragmatic observation is this: continuing
ketamine infusion postoperatively for the first 24 hours is beneficial, but it will require
monitoring the patient and availability of qualified anesthesia personnel and equipment (Zakine
19

et al., 2008). Hence, if proper postoperative monitoring is not feasible, based on the results from
Loftus et al. (2010) and Nielsen et al. (2017), ketamine infusion could be continued until the end
of the surgery to ensure the safety of the patient while attaining acceptable efficacy and
effectiveness.
In our literature review, we confirmed that ketamine use was effective, in that the drug
provided effective analgesia in opioid dependent patients, which may be potentiated by the use
of a continuous intra- and postoperative infusion. When ketamine was used as an adjunct to
decrease opioid use and pain level, the literature demonstrated that bolus doses between 0.2 to
0.5 mg/kg were effective. Furthermore, ketamine was safe and easy to administer. Side effects
secondary to ketamine administration was not different between these doses and none of the
reviewed studies reported a significant difference on side effects on patients who received
ketamine. Based on the acceptable side effect profile and the improved efficacy of ketamine
doses in Loftus et al. (2010), Nielsen et al. (2017) and Zakine et al. (2008), 0.5 mg/kg bolus
doses appear to be effective analgesic doses for opioid-dependent patients. Regarding the
continuous infusion, a range of 0.2 to 0.6 mg/kg/hour appeared effective based on this literature
review with comparable side effect profile and improved efficacy with higher doses (Nielsen et
al., 2017; Zakine et al., 2008). To summarize: an intraoperative infusion of 0.5-0.6 mg/kg,
decreased to 0.12-0.25 mg/kg per hour after the conclusion of surgery, if infusion will be
continued in the PACU, appeared safe and effective. More research is required to clarify the
appropriate dose of ketamine in this setting.
The trials on the effects of ketamine in decreasing depressive symptoms are still ongoing
but appear to be rich with the possibility of focusing on the unique care of an opioid-dependent
patient with chronic pain suffering from depression as a co-diagnosis. The trials have the
20

potential to bring a strong focus on the perioperative mental health issues that patients in this
population face and explore measures to improve prognosis and widen the focus that ketamine
offers for mental health (Zhou et al., 2018).
Conclusion
This project has reviewed anesthetic considerations for the use of ketamine as an adjunct
to the management of acute perioperative analgesia in a population of patients with
comorbidities of chronic pain and opioid dependence. These patients are at risk because of their
propensity to allodynia and hyperalgesia. Therefore, the management of analgesia in this
population is of paramount importance and is challenging because of the complexity of their pain
care, coupled with the lack of consensus recommendations in the vast range of literature
available. Furthermore, the propensity of this patient population to depression is well known and
though not the primary focus of this study, the emerging anti-depressant effects of ketamine
increase the drug’s attractiveness as an adjunct to multimodal analgesia in this context
(Dubovsky, 2018; Kraus et al., 2019).
In our review of the relevant literature, we discovered ketamine might be safely added to
these patient’s pain regimen unless medically contraindicated, according to specific dosage and
infusion protocol considerations. Ketamine is an effective analgesic adjunct for these patients,
acting through multiple mechanisms and more research is indicated in the following areas. First,
decreased opioid use due to ketamine administration should be more closely investigated, as this
was found to vary in Loftus et al. (2010) as opposed to Barreveld et al. (2013). Second, the
benefit of providing ketamine infusion postoperatively should be pragmatically compared to the
cons of requiring qualified anesthesia personnel and equipment to monitor the patient. Third, the
21

continued postoperative infusion dosing of ketamine in the PACU should be more closely
investigated according to a gap in the literature in Nielsen et al. (2017) and Zakine et al. (2008).

22

References
Alam, A., & Juurlink, D. (2015). The prescription opioid epidemic: an overview for
anesthesiologists. Canadian Journal of Anaesthesia., 63(1), 61–68.
Avidan, M., Maybrier H., Abdallah A., Jacobsohn E., Vlisides P., Pryor K., Veselis R., Grocott
H., Emmert D., Rogers E., Downey R., Yulico H., Noh G., Lee Y., Waszynski C., Arya
V., Pagel P., Hudetz J., Muench M., …, Mashour G. (2017). Intraoperative ketamine for
prevention of postoperative delirium or pain after major surgery in older adults: an
international, multicentre, double-blind, randomised clinical trial. The Lancet.,
390(10091), 267–275.
Barreveld, A., Correll, D., Liu X., Max, B., McGowan, J., Shovel, L., Wasan, A., Nedeljkovic, S.
(2013). Ketamine decreases postoperative pain scores in patients taking opioids
for chronic pain: results of a prospective, randomized, double-blind study. Pain
Medicine., 14(6), 925–934
Braun, M., & Kassop, D. (2019). Cardiovascular Disease: Lower Extremity Deep Venous
Thrombosis. FP Essent, 479, 21–29.
Brummett, C., Waljee, J., Goesling, J., Moser, S., Lin, P., Englesbe, M., Bohnert, A., Kheterpal,
S., Nallamothu, B. (2017). New Persistent Opioid Use After Minor and Major Surgical
Procedures in US Adults. JAMA Surgery, 152(6), e170504–e170504.
Chizh, Boris A (2007). Low dose ketamine: a therapeutic and research tool to explore
N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways.
Journal of psychopharmacology /. 21(3):259-271.
Chu, L., Angst, M., & Clark, D. (2008). Opioid-induced hyperalgesia in humans: molecular
mechanisms and clinical considerations. The Clinical Journal of Pain, 24(6), 479–496.
23

Davis, M., Lin, L., Liu, H., & Sites, B. (2017). Prescription Opioid Use among Adults with
Mental Health Disorders in the United States. The Journal of the American Board of
Family Medicine JABFM., 30(4), 407–417.
Dowell D, Haegerich TM, Chou R. (2016) CDC Guideline for Prescribing Opioids for Chronic
Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49.
Dubovsky, S. L. (2018). What Is New about New Antidepressants? Psychotherapy and
Psychosomatics, 87(3), 129–139.
Elena J. Koepke, Erin L. Manning, Timothy E. Miller, Arun Ganesh, David G. A. Williams, &
Michael W. Manning. (2018). The rising tide of opioid use and abuse: the role of the
anesthesiologist. Perioperative Medicine., 7.
Gan, T., Habib, A., Miller, T., White, W., & Apfelbaum, J. (2014). Incidence, patient
satisfaction, and perceptions of post-surgical pain: results from a US national survey.
Current Medical Research and Opinion., 30(1), 149–160.
Gorlin, A., Rosenfeld, D., & Ramakrishna, H. (2016.). Intravenous sub-anesthetic ketamine for
perioperative analgesia. Journal of Anesthesiology Clinical Pharmacology., 32(2),
160–167.
Haas, D., & Harper, D. (1992). Ketamine: a review of its pharmacologic properties and use in
ambulatory anesthesia. Anesthesia Progress., 39(3), 61–68.
Hisham, R., Ng, C. J., Liew, S. M., Hamzah, N., & Ho, G. J. (2016). Why is there variation in
the practice of evidence-based medicine in primary care? A qualitative study. BMJ open,
6(3), e010565.
Hu, Y., Xiang, Y., Fang, J., Zu, S., Sha, S., Shi, H., Ungvari, G., Correll, C., Chiu, H., Xue, Y.,
Tian, T., Wu, A., Ma, X., Wang, G. (2016). Single i.v. ketamine augmentation of newly
24

initiated escitalopram for major depression: results from a randomized, placebo-
controlled 4-week study. Psychological Medicine, 46(3), 623–635.
Inouye, S. (2007). Delirium in older persons. The New England Journal of Medicine.,
354(11), 1157–1165.
Jackman, C. (2019.). Perioperative Pain Management for the Chronic Pain Patient With
Long-Term Opioid Use. Orthopedic Nursing., 38(2), 159–163.
Joly, V., Richebe, P., Guignard, B., Fletcher, D., Maurette, P., Sessler, D., & Chauvin, M.
(2005). Remifentanil-induced postoperative hyperalgesia and its prevention with small-
dose ketamine. Anesthesiology., 103(1), 147–155.
Kessler, E., Shah, M., Gruschkus, S., & Raju, A. (2013). Cost and quality implications of
opioid-based postsurgical pain control using administrative claims data from a large
health system: opioid-related adverse events and their impact on clinical and economic
outcomes. Pharmacotherapy : Official Journal of the American College of Clinical
Pharmacy., 33(4), 383–391.
Kishimoto, T., Chawla, J. M., Hagi, K., Zarate, C. A., Kane, J. M., Bauer, M., & Correll, C. U.
(2016). Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor
antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and
time trajectories. Psychological medicine, 46(7), 1459–1472.
Koepke, E., Manning, E., Miller, T., Ganesh, A., Williams, D., & Manning, M. (2018). The
rising tide of opioid use and abuse: the role of the anesthesiologist. Perioperative
medicine (London, England), 7, 16.

25

Kraus, C., Kadriu, B., Lanzenberger, R., Zarate, C. A., Jr, & Kasper, S. (2019). Prognosis and
improved outcomes in major depression: a review. Translational psychiatry, 9(1), 127.
Kurd, M., Kreitz, T., Schroeder, G., & Vaccaro, A. (2017). The Role of Multimodal Analgesia in
Spine Surgery. Journal of the American Academy of Orthopaedic Surgeons., 25(4),
260–268.
Leung, P., Macdonald, E., Stanbrook, M., Dhalla, I., & Juurlink, D. (2017). A 1980 Letter on the
Risk of Opioid Addiction. The New England Journal of Medicine., 376(22), 2194–2195.
Loftus, R., Yeager, M., Clark, J., Brown, J., Abdu, W., Sengupta, D., Beach, M. (2010).
“Intraoperative Ketamine Reduces Perioperative Opiate Consumption in Opiate-
Dependent Patients with Chronic Back Pain Undergoing Back Surgery.”
Anesthesiology.113.3 639–646.
Love, T. (2013). Variation in medical practice: Literature review and discussion. Wellington,
New Zealand: Health Quality & Safety Commission.
Maher, D., Chen, L., & Mao, J. (2017). Intravenous Ketamine Infusions for Neuropathic Pain
Management: A Promising Therapy in Need of Optimization. Anesthesia & Analgesia,
124(2), 661–674.
Moussavi, S., Chatterji, S., Verdes, E., Tandon, A., Patel, V., & Ustun, B. (2007). Depression,
chronic diseases, and decrements in health: results from the World Health Surveys. The
Lancet., 370(9590), 851–858.
Niesters, M., Martini, C., & Dahan, A. (2014). Ketamine for chronic pain: risks and benefits.
British Journal of Clinical Pharmacology BJCP., 77(2), 357–367
Nielsen, R., Fomsgaard, J., Siegel, H., Martusevicius, R., Nikolajsen, L., Dahl, J., & Mathiesen,
O. (2017). Intraoperative ketamine reduces immediate postoperative opioid consumption
26

after spinal fusion surgery in chronic pain patients with opioid dependency: a
randomized, blinded trial. Pain., 158(3), 463–470.
Phillips JK, Ford MA, Bonnie RJ, National Academies of Sciences, E., Health and Medicine
Division, Board on Health Sciences Policy, & Committee on Pain Management and
Regulatory Strategies to Address Prescription Opioid Abuse. (2017). Pain Management
and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of
Prescription Opioid Use.
Porter J, Jick H. Addiction rare in patients treated with narcotics. (1980.). New England Journal
of Medicine., 302(2).
Rosero, E., & Joshi, G. (2014). Preemptive, preventive, multimodal analgesia: what do they
really mean? Plastic & Reconstructive Surgery, 134(4 Suppl 2), 85S–93S.
Rudd, R., Aleshire, N., Zibbell, J., & Gladden, R. (2016). Increases in Drug and Opioid
Overdose Deaths--United States, 2000-2014. Morbidity and Mortality Weekly Report
MMWR /, 64(50-51), 1378–1382.
Rudd, R., Seth, P., David, F., & Scholl, L. (2016). Increases in Drug and Opioid-Involved
Overdose Deaths - United States, 2010-2015. Morbidity and Mortality Weekly Report
MMWR /, 65(50-51), 1445–1452.
Sabatowski, R., Schäfer, D., Kasper, S., Brunsch, H., & Radbruch, L. (2004). Pain treatment: a
historical overview. Current Pharmaceutical Design., 10(7), 701–716.
Safety Council, N. (n.d.). Odds of Dying. Retrieved 2017, from
https://injuryfacts.nsc.org/all-injuries/preventable-death-overview/odds-of-dying/
27

Schwenk, E., & Mariano, E. (2018). Designing the ideal perioperative pain management plan
starts with multimodal analgesia. The Korean Society of Anesthesiologists, 71(5),
345–352
Schwenk, E., Viscusi, E., Buvanendran, A., Hurley, R., Wasan, A., Narouze, S., Bhatia, A.,
Davis, F., Hooten, W., Cohen, S. (2018). Consensus Guidelines on the Use of
Intravenous Ketamine Infusions for Acute Pain Management From the American Society
of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine,
and the American Society of Anesthesiologists. Regional Anesthesia and Pain Medicine,
43(5), 456–466.
Shea, R., Brooks, J., Dayhoff, N., & Keck, J. (2002). Pain intensity and postoperative pulmonary
complications among the elderly after abdominal surgery. Heart & Lung the Journal of
Acute and Critical Care., 31(6), 440–449.
Singh, J., Fedgchin, M., Daly, E., De Boer, P., Cooper, K., Lim, P., Pinter, C., Murrough, J.,
Sanacora, G., Shelton, R., Kurian, B., Winokur, A., Fava, M., Manji, H., Drevets, W.,
Van Nueten, L. (2016). A Double-Blind, Randomized, Placebo-Controlled, Dose-
Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant
Depression. The American Journal of Psychiatry., 173(8), 816–826.
Tan, W., Yu, J., Feaman, S., McAllister, J., Kahan, L., Quasebarth, M., Blatnik, J., Eagon, J.,
Awad, M., Brunt, L. (2018). Opioid Medication Use in the Surgical Patient: An
Assessment of Prescribing Patterns and Use. Journal of the American College of
Surgeons., 227(2), 203–211. Urban, M., Ya Deau, J., Wukovits, B., & Lipnitsky, J.
(2008). Ketamine as an adjunct to postoperative pain management in opioid tolerant
28

patients after spinal fusions: a prospective randomized trial. HSS Journal: the
Musculoskeletal Journal of Hospital for Special Surgery., 4(1), 62–65.
Verbeek, J., Van Dijk, F., Malmivaara, A., Hulshof, C., Räsänen, K., Kankaanpää, E., & Mukala,
K. (2002). Evidence-based medicine for occupational health. Scandinavian Journal of
Work, Environment & Health, 28(3), 197-204.
Warfield, C., & Kahn, C. (1995). Acute pain management. Programs in U.S. hospitals and
experiences and attitudes among U.S. adults. Anesthesiology., 83(5), 1090–1094.
Zakine, J., Samarcq, D., Lorne, E., Moubarak, M., Montravers, P., Beloucif, S., & Dupont, H.
(2008). Postoperative ketamine administration decreases morphine consumption in major
abdominal surgery: a prospective, randomized, double-blind, controlled study.
Anesthesia & Analgesia, 106(6), 1856–1861.
Zhou, Y., Peng, Y., Fang, J., Sun, W., Zhang, G., Zhen, L., Wang, G., Han, R. (2018). Effect of
low-dose ketamine on PerioperAtive depreSsive Symptoms in patients undergoing
Intracranial tumOr resectioN (PASSION): study protocol for a randomized controlled
trial. Trials, 19(1).

29

Appendix
Appendix A
Literature Matrix of Contemporary Publications
APA Reference Summary of Main Concept Quantitat
ive or
Qualitative
Research?
Methods
(Design,
instruments,
questionnaires)
Main Findings of the Study Application for 694a
Alam, A., & Juurlink,
D. (2015). The
prescription opioid
epidemic: an overview
for anesthesiologists.
Canadian Journal of
Anaesthesia., 63(1), 61–
68.
Review of the historical
context and epidemiology
surrounding the North
American prescription
opioid crisis, summary of
the evidence regarding the
benefits and harms of long-
term opioid therapy for non-
cancer pain and outlines
ways in which
anesthesiologists may help
ameliorate the problem.
Qualitative Literature review In the 1980s and early 1990s, opioids were
infrequently used for the treatment of
chronic pain. Thereafter, however,
physicians were gradually inculcated with
the message that long-term opioid therapy
was a safe and effective treatment option
for patients with chronic non-cancer pain.
Pharmaceutical companies supported this
growing movement and employed
aggressive and sometimes misleading
marketing strategies for new opioid
formulations. As a result, the practice of
prescribing opioids flourished in the late
1990s. The surge in prescribing opioids
was accompanied by a marked increase in
opioid-related morbidity and mortality.
This change in practice transpired despite
the absence of randomized trials showing
clinically significant benefit from the
long-term use of opioids. Subsequently,
however, a large and growing body of
evidence has emerged quantifying the
Anesthesiologists are
well positioned to
take a leadership role
in the management of
postoperative
discharge opioid
therapy in an effort to
curb the
overutilization of
opioids. Furthermore,
anesthesiologists who
regularly prescribe
opioids for chronic
pain patients should
appreciate the limited
evidence base for this
practice and
communicate the
risks of opioid
therapy to their
patients.
30

harms associated with long-term opioid
therapy.
31

Avidan, M., Maybrier
H., Abdallah A.,
Jacobsohn E., Vlisides
P., Pryor K., Veselis R.,
Grocott H., Emmert
D., Rogers E., Downey
R., Yulico H., Noh G.,
Lee Y., Waszynski C.,
Arya V., Pagel P.,
Hudetz J., Muench M.,
…, Mashour G. (2017).
Intraoperative ketamine
for prevention of
postoperative delirium
or pain after major
surgery in older adults:
an international,
multicentre, double-
blind, randomised
clinical trial. The
Lancet, 390(10091),
267-275.
Assess the effectiveness of
ketamine for prevention of
postoperative delirium in
older adults.

Quantitative

International
Double blind
Multicentre
Randomized
clinical trial

Between Feb 6, 2014, and June 26, 2016,
1360 patients were assessed, and 672 were
randomly assigned, with 222 in the
placebo group, 227 in the 0·5 mg/kg
ketamine group, and 223 in the 1·0 mg/kg
ketamine group. There was no difference
in delirium incidence between patients in
the combined ketamine groups and the
placebo group. There were more
postoperative hallucinations (p=0·01) and
nightmares (p=0·03) with increasing
ketamine doses compared with placebo.
Adverse events (cardiovascular, renal,
infectious, gastrointestinal and bleeding),
whether viewed individually or
collectively did not differ significantly
across groups.
A single
subanesthetic dose of
ketamine did not
decrease delirium in
older adults after
major surgery and
might cause harm by
inducing negative
experiences.
32

Barreveld, A., Correll,
D., Liu X., Max, B.,
McGowan, J., Shovel,
L., Wasan, A.,
Nedeljkovic, S. (2013).
Ketamine decreases
postoperative pain
scores in patients taking
opioids for chronic pain:
results of a prospective,
randomized, double-
blind study. Pain
Medicine., 14(6), 925–
934
Patients prescribed opioids
for chronic pain may suffer
from inadequate
postoperative pain control.
Ketamine is an adjuvant
demonstrating analgesic and
opioid-sparing effects.
Hypothesis: an intravenous
ketamine infusion in
addition to opioid-based
patient-controlled analgesia
(PCA) improves
postoperative pain relief in
this patient population.
Quantitative Prospective
Randomized
Double-blind
study
Fifty-nine patients were included in the
analysis. Baseline patient characteristics
were similar with the exception of age.
Patients using ketamine had decreased
"average" pain scores (percent change
between postoperative and preoperative
NRS) after surgery. There were no
differences in "worst" or "least" pain
scores or postoperative opioid use. Side
effects between groups were similar.
A postoperative
ketamine infusion at
0.2 mg/kg/hour in
addition to opioids
results in a
statistically
significant reduction
of "average" pain
scores in patients
undergoing surgery
who take opioids for
chronic pain.
However, "least" and
"worst" pain scores
and the amount of
opioid used
postoperatively did
not differ between
groups. Thus, the use
of a postoperative
ketamine infusion at
0.2 mg/kg/hour
provides limited
benefit.
33

Braun, M., & Kassop,
D. (2019).
Cardiovascular Disease:
Lower Extremity Deep
VenousThrombosis. FP
Essent, 479, 21–29.
Risk factors for deep venous
thrombosis (DVT) include
immobility, recent or
current hospitalization,
recent surgery, recent
infection and cancer.
Patients with suspected
venous thromboembolism
should be evaluated with the
Wells score or modified
Wells score (which adds a
previous DVT) to determine
the likelihood of DVT.
Qualitative Case report A low or moderate probability score and a
normal D-dimer test result exclude DVT.
If the score indicates that DVT is likely,
patients should undergo Doppler
ultrasonography (US). If US reveals DVT
in a proximal (ie, in the knee or above)
vein, anticoagulation should be started
unless contraindicated. If the DVT is distal
(ie, below the knee), patients can be
started on anticoagulation or monitored
with repeat US and started on
anticoagulation if the clot extends
proximally.
Risk factors for deep
venous thrombosis
(DVT) and treatment
perioperatively.
Chizh, Boris A (2007).
Low dose ketamine: a
therapeutic and research
tool to explore N-
methyl-D-aspartate
(NMDA) receptor-
mediated plasticity in
pain pathways. Journal
of psychopharmacology
/. 21(3):259-271.
Ketamine belongs to the
class of uncompetitive
antagonists and blocks the
receptor by binding to a
specific site within the
NMDA receptor channel
when it is open. Ketamine
has served as a useful tool
to provide a compelling
rationale for developing
other NMDA antagonists.
Qualitative Literature review As the most potent and selective NMDA
antagonist currently available for human
use, ketamine has been an extremely
valuable tool for investigating the role of
NMDA receptors in physiological and
pathological states in humans. It has
served to unravel mechanisms of chronic
pain and provide evidence of NMDA
receptor-mediated plasticity and central
sensitization in human pain states.
Although it has not been possible to
separate safely the pain relief from the
side effects of the drug and clinical use of
ketamine as a pain treatment is very
limited, ketamine data provide a rationale
for developing novel NMDA antagonists
and other agents targeting central
sensitization mechanisms. Should a
compound with a satisfactory profile be
found, therapeutic areas for its use can
Ketamine’s validity
for investigating the
role of NMDA
receptors.
34

also be defined on the basis of the
ketamine efficacy data.
Chu, L., Angst, M., &
Clark, D. (2008).
Opioid-induced
hyperalgesia in
humans: molecular
mechanisms and
clinical considerations.
The Clinical Journal of
Pain., 24(6), 479–496.

Opioid-induced
hyperalgesia (OIH) is most
broadly defined as a state of
nociceptive sensitization
caused by exposure to
opioids. The state is
characterized by a
paradoxical response
whereby a patient receiving
opioids for the treatment of
pain may actually become
more sensitive to certain
painful stimuli.
Quantitative Literature review
The type of pain experienced may or may
not be different from the original
underlying painful condition. Although the
precise molecular mechanism is not yet
understood, it is generally thought to result
from neuroplastic changes in the
peripheral and central nervous systems
that lead to sensitization of pronociceptive
pathways.
Clinicians should
suspect expression of
OIH when opioid
treatment effect
seems to wane in the
absence of disease
progression,
particularly if found
in the context of
unexplained pain
reports or diffuse
allodynia
unassociated with the
pain as previously
observed.
35

Davis, M., Lin, L., Liu,
H., & Sites, B. (2017).
Prescription Opioid
Use among Adults
with Mental Health
Disorders in the United
States. The Journal of
the American Board of
Family Medicine
JABFM., 30(4), 407–
417.
The extent to which adults
with mental health disorders
in the United States receive
opioids has not been
adequately reported.
Quantitative Cross-sectional
study
Among the the 38.6 million Americans
with mental health disorders, 18.7% (7.2
million of 38.6 million) use prescription
opioids. Adults with mental health
conditions receive 51.4% (60 million of
115 million prescriptions) of the total
opioid prescriptions distributed in the
United States each year. Compared with
adults without mental health disorders,
adults with mental health disorders were
significantly more likely to use opioids =).
In adjusted analyses, having a mental
health disorder was associated with
prescription opioid use overall.
The 16% of
Americans who have
mental health
disorders receive over
half of all opioids
prescribed in the
United States.
Improving pain
management among
this population is
critical to reduce
national dependence
on opioids.
Dowell D, Haegerich
TM, Chou R. (2016)
CDC Guideline for
Prescribing Opioids for
Chronic Pain —
United States, 2016.
MMWR Recomm Rep
2016;65(No. RR-1):1–
49.
This guideline provides
recommendations for
primary care clinicians who
are prescribing opioids for
chronic pain outside of
active cancer treatment,
palliative care and end-of-
life care.
Quantitative GRADE
framework
Systematic
review
It is important that patients receive
appropriate pain treatment with careful
consideration of the benefits and risks of
treatment options. This guideline is
intended to improve communication
between clinicians and patients about the
risks and benefits of opioid therapy for
chronic pain, improve the safety and
effectiveness of pain treatment, and reduce
the risks associated with long-term opioid
therapy, including opioid use disorder,
overdose and death.
The guideline
addresses 1) when to
initiate or continue
opioids for chronic
pain; 2) opioid
selection, dosage,
duration, follow-up
and discontinuation;
and 3) assessing risk
and addressing harms
of opioid use.
36

Dubovsky, S. L.
(2018). What Is New
about New
Antidepressants?
Psychotherapy and
Psychosomatics, 87(3),
129–139.
Depressed patients and their
physicians naturally expect
that each new antidepressant
that reaches the market will
represent a conceptual and
therapeutic advance over
previous medications. This
review attempts to
determine how realistic this
expectation may be while
reviewing dispassionately
the validity of the
assumptions that underlie
the development of new
antidepressants and the data
supporting their differential
effectiveness.
Quantitative Literature review New antidepressants may be more or less
equivalent in overall outcomes, but they
may have differential effects on different
domains of depressive disorders. Defining
specific dimensions of depressive
disorders would facilitate studying the
relative benefit of one or a combination of
medications in different depressive
subtypes.
Ketamine and its role
as an antidepressant.
Elena J. Koepke, Erin
L. Manning, Timothy
E. Miller, Arun
Ganesh, David G. A.
Williams, & Michael
W. Manning. (2018).,
The rising tide of
opioid use and abuse:
the role of the
anesthesiologist.
Perioperative
Medicine., 7.
Opioids have many
undesirable side effects,
including potential for
misuse, or opioid use
disorder. Anesthesiologists
and surgeons employ
several methods to decrease
unnecessary opioid use,
opioid-related adverse
events and side effects in
the perioperative period.
Quantitative Literature review Multimodal analgesia, enhanced recovery
pathways and regional anesthesia are key
tools in working towards optimal opioid
stewardship and the ideal of effective
analgesia without undesirable sequelae.
Multimodal analgesia
with ketamine as an
adjunct.
37

Gan, T., Habib, A.,
Miller, T., White, W.,
& Apfelbaum, J.
(2014). Incidence,
patient satisfaction,
and perceptions of
post-surgical pain:
results from a US
national survey.
Current Medical
Research and
Opinion., 30(1), 149–
160.
During the past two
decades, professional
associations, accrediting
bodies and payers have
made post-surgical pain
treatment a high priority. In
light of the disappointing
findings in previous
surveys, a survey was
conducted to assess patient
perceptions and characterize
patient experiences/levels of
satisfaction with post-
surgical pain management.
Qualitative Survey included
a random sample
of US adults who
had undergone
surgery within 5
years from the
survey date.
Of the 300 participants, ∼86%
experienced pain after surgery; of these,
75% had moderate/extreme pain during
the immediate post-surgical period, with
74% still experiencing these levels of pain
after discharge. Post-surgical pain was the
most prominent pre-surgical patient
concern and nearly half reported they had
high/very high anxiety levels about pain
before surgery. Approximately 88%
received analgesic medications to manage
pain; of these, 80% experienced adverse
effects and 39% reported moderate/severe
pain even after receiving their first dose.
Despite heightened
awareness and
clinical advancements
in pain management,
there has been little
improvement in post-
surgical analgesia as
measured by this
survey of post-
surgical patients.
Gorlin, A., Rosenfeld,
D., & Ramakrishna, H.
(2016.). Intravenous
sub-anesthetic
ketamine for
perioperative
analgesia. Journal of
Anaesthesiology
Clinical
Pharmacology., 32(2)
160–167.
Ketamine, an N-methyl-d-
aspartate antagonist, blunts
central pain sensitization at
sub-anesthetic doses (0.3
mg/kg or less) and has been
studied extensively as an
adjunct for perioperative
analgesia.
Ketamine Literature review At sub-anesthetic doses, ketamine has a
minimal physiologic impact though it is
associated with a low incidence of mild
psychomimetic symptoms as well as
nystagmus and double vision.
Contraindications to its use exist and due
to ketamine's metabolism, caution should
be exercised in patients with renal or
hepatic dysfunction. Sub-anesthetic
ketamine improves pain scores and
reduces perioperative opioid consumption
in a broad range of surgical procedures. In
addition, there is evidence that ketamine
may be useful in patients with opioid
tolerance and for preventing chronic
postsurgical pain.
Ketamine’s
relationship with
reduced pain; chronic
pain.
38

Haas, D., & Harper, D.
(1992). Ketamine: a
review of its
pharmacologic
properties and use in
ambulatory anesthesia.
Anesthesia Progress.,
39(3), 61–68.
Ketamine, a dissociative
anesthetic, has several
advantageous physical,
pharmacokinetic and
pharmacodynamic
properties.
Literature review Ketamine can be used to induce
anesthesia, sedation, analgesia, and
amnesia. Ketamine can maintain
functional residual capacity, induce
bronchodilation and avoid cardiovascular
depression. However, adverse effects have
been demonstrated, such as cardiovascular
stimulation and unpleasant emergence
phenomena, both of which may be
modulated by supplementation with
benzodiazepines.
An increase in the use
of ketamine for
ambulatory anesthesia
has recently been
advocated. This
review of the
literature supports the
use of ketamine as an
effective agent for
selected anesthetic
procedures.
Hisham, R., Ng, C. J.,
Liew, S. M., Hamzah,
N., & Ho, G. J. (2016).
Why is there variation
in the practice of
evidence-based
medicine in primary
care? A qualitative
study. BMJ open, 6(3),
e010565.
To explore the factors,
including barriers and
facilitators, influencing the
practice of evidence-based
medicine (EBM) across
various primary care
settings in Malaysia based
on the doctors' views and
experiences.
Qualitative The qualitative
study was used to
answer the
research
question. 37
primary care
physicians
participated in
six focus group
discussions and
six individual in-
depth interviews.
The doctors in this study were aware of
the importance of EBM but seldom
practiced it. Three main factors influenced
the implementation of EBM in the doctors'
daily practice. First, there was a lack of
knowledge and skills in searching for and
applying evidence. Second, workplace
culture influenced doctors' practice of
EBM. Third, some doctors considered
EBM as a threat to good clinical practice.
They were concerned that rigid application
of evidence compromised personalised
patient care and felt that EBM did not
consider the importance of clinical
experience.
Strategies targeting
barriers at the practice
level should be
considered when
implementing EBM
in primary care.
39

Hu, Y., Xiang, Y.,
Fang, J., Zu, S., Sha,
S., Shi, H., Ungvari,
G., Correll, C., Chiu,
H., Xue, Y., Tian, T.,
Wu, A., Ma, X., Wang,
G. (2016). Single i.v.
ketamine augmentation
of newly initiated
escitalopram for major
depression: results
from a randomized,
placebo-controlled 4-
week study.
Psychological
Medicine, 46(3), 623–
635.
While oral antidepressants
reach efficacy after weeks,
single-dose intravenous
(i.v.) ketamine has rapid, yet
time-limited antidepressant
effects. This study aimed to
determine the efficacy and
safety of single-dose i.v.
ketamine augmentation of
escitalopram in major
depressive disorder (MDD).
Quantitative Randomized
control trial
Placebo-
controlled
By 4 weeks, more escitalopram +
ketamine-treated than escitalopram +
placebo-treated patients responded and
remitted, with significantly shorter time to
response. Compared to escitalopram +
placebo, escitalopram + ketamine was
associated with significantly lower
MADRS scores from 2 h to 2 weeks. Only
YMRS scores increased significantly with
ketamine augmentation without significant
BPRS or CADSS elevation.
Single-dose i.v.
ketamine
augmentation of
escitalopram was safe
and effective in
severe MDD, holding
promise for speeding
up early oral
antidepressant
efficacy.
Inouye, S. (2007).
Delirium in older
persons. The New
England Journal of
Medicine., 354(11),
1157–1165.

This report examines
current clinical practice in
delirium, identifies areas of
controversy and highlights
areas for future research.
Quantitative Literature
Review
Epidemiology and diagnostic criteria for
delirium, difference between dementia and
delirium, clinical characteristics and using
delirium as an indicator for quality care.
The difference
between delirium and
dementia and how to
treat it when related
to ketamine.
40

Jackman, C. (2019.).
Perioperative Pain
Management for the
Chronic Pain Patient
With Long-Term
Opioid Use.
Orthopedic Nursing.,
38(2), 159–163.
This article aims to review
the challenges presented by
these complex patients and
provide strategies for
treating acute postoperative
pain in opioid-tolerant
patients.
Quantitative Literature
Review
In the United States nearly one in four
patients presenting for surgery reports
current opioid use. Many of these patients
suffer from chronic pain disorders and
opioid tolerance or dependence. Opioid
tolerance and preexisting chronic pain
disorders present unique challenges
concerning postoperative pain
management. These patients benefit from
providers who are not only familiar with
multimodal pain management and skilled
in the assessment of acute pain, but also
empathetic to their specific struggles.
Chronic pain patients often face stigmas
surrounding their opioid use and this may
lead to underestimation and
undertreatment of their pain.
Ketamine’s
usefulness as an
adjunct to chronic
pain.
Joly, V., Richebe, P.,
Guignard, B., Fletcher,
D., Maurette, P.,
Sessler, D., &
Chauvin, M. (2005).
Remifentanil-induced
postoperative
hyperalgesia and its
prevention with small-
dose ketamine.
Anesthesiology.,
103(1), 147–155.
Remifentanil-induced
secondary hyperalgesia has
been documented
experimentally in both
animals and healthy human
volunteers, but never
clinically. This study tested
the hypothesis that
increased pain sensitivity
assessed by peri incisional
allodynia and hyperalgesia
can occur after relatively
large-dose intraoperative
remifentanil and that small-
dose ketamine prevents this
hyperalgesia.
Quantitative Randomized
Control Trial
Hyperalgesia to von Frey hair stimulation
adjacent to the surgical wound and
morphine requirements were larger and
allodynia to von Frey hair stimulation was
greater in the large-dose remifentanil
group compared with the other two
groups, which were comparable. There
were no significant differences in pain,
pressure pain detection threshold with an
algometer, peak flow, cognitive tests, or
side effects.
A relatively large
dose of intraoperative
remifentanil triggers
postoperative
secondary
hyperalgesia.
Remifentanil-induced
hyperalgesia was
prevented by small-
dose ketamine,
implicating an N-
methyl-d-aspartate
pain-facilitator
process.
41

Kessler, E., Shah, M.,
Gruschkus, S., & Raju,
A. (2013). Cost and
quality implications of
opioid-based
postsurgical pain
control using
administrative claims
data from a large
health system: opioid-
related adverse events
and their impact on
clinical and economic
outcomes.
Pharmacotherapy :
Official Journal of the
American College of
Clinical Pharmacy.,
33(4), 383–391.
To determine the prevalence
of postsurgical opioid use in
the inpatient setting, to
ascertain the frequency of
and risk factors for opioid-
related adverse drug events
(ORADEs) among patients
who received opioids and to
evaluate the impact of
ORADEs on clinical and
economic outcomes.
Quantitative
Retrospective
cohort study
using
administrative
data.

Patients were evaluated for receipt of
postsurgical opioids. Among all surgical
patients, 36,529 (98.6%) of patients
received opioids, of whom 4955 (13.6%)
experienced an ORADE. Increased risk of
ORADEs was associated with age 65
years or older, male sex, obesity,
presurgery opioid use and higher score on
Charlson Comorbidity Index. Patients with
an ORADE had a 55% longer length of
stay, 47% higher costs of care, 36%
increased risk of 30-day readmission and
3.4 times higher risk of inpatient mortality
than did patients who did not experience
an ORADE.
The observed
negative outcomes of
ORADEs and their
impact on patients
and the health care
system should be
considered when
evaluating the
balance between
effectively managing
postsurgical pain
while minimizing the
risk of ORADEs.
42

Kishimoto, T., Chawla,
J. M., Hagi, K., Zarate,
C. A., Kane, J. M.,
Bauer, M., & Correll,
C. U. (2016). Single-
dose infusion ketamine
and non-ketamine N-
methyl-d-aspartate
receptor antagonists
for unipolar and
bipolar depression: a
meta-analysis of
efficacy, safety and
time trajectories.
Psychological
medicine, 46(7), 1459–
1472.

Ketamine and non-ketamine
N-methyl-d-aspartate
receptor antagonists
(NMDAR antagonists)
recently demonstrated
antidepressant efficacy for
the treatment of refractory
depression, but effect sizes,
trajectories and possible
class effects are unclear.
Quantitative Literature
Review
A total of 14 RCTs were meta-analysed.
Ketamine reduced depression significantly
more than placebo/pseudo-placebo
beginning at 40 min, peaking at day 1.
Non-ketamine NMDAR antagonists were
superior to placebo only on days 5-8.
Compared with placebo/pseudo-placebo,
ketamine led to significantly greater
response (40 min to day 7) and remission
(80 min to days 3-5). Non-ketamine
NMDAR antagonists achieved greater
response at day 2 and days 3-5. All-cause
discontinuation was similar between
ketamine or non-ketamine NMDAR
antagonists and placebo. Although some
adverse effects were more common with
ketamine/NMDAR antagonists than
placebo, these were transient and
clinically insignificant.
A single infusion of
ketamine, but less so
of non-ketamine
NMDAR antagonists,
has ultra-rapid
efficacy for MDD and
BD, lasting for up to
1 week. Development
of easy-to-administer,
repeatedly given
NMDAR antagonists
without risk of brain
toxicity is of critical
importance.
Kraus, C., Kadriu, B.,
Lanzenberger, R.,
Zarate, C. A., Jr, &
Kasper, S. (2019).
Prognosis and
improved outcomes in
major depression: a
review. Translational
psychiatry, 9(1), 127.

Treatment outcomes for
major depressive disorder
(MDD) need to be
improved. Presently, no
clinically relevant tools
have been established for
stratifying subgroups or
predicting outcomes. This
literature review sought to
investigate factors closely
linked to outcome and
summarize existing and
novel strategies for
improvement.
Quantitative Literature
review
Early recognition and treatment are
crucial, as duration of untreated
depression correlates with worse
outcomes. Early improvement is
associated with response and remission,
while comorbidities prolonged course of
illness. Strategies such as managing risk
factors, improving clinical trial
methodology and designing structured
step-by-step treatments are also beneficial.

Novel rapid-acting
antidepressants, such
as ketamine, may also
constitute a paradigm
shift in treatment
optimization for
MDD.
43

Kurd, M., Kreitz, T.,
Schroeder, G., &
Vaccaro, A. (2017). The
Role of Multimodal
Analgesia in Spine
Surgery. Journal of the
American Academy of
Orthopaedic Surgeons.,
25(4), 260–268.

Optimal postoperative pain
control allows for faster
recovery, reduced
complications and improved
patient satisfaction.
Historically, pain
management after spine
surgery relied heavily on
opioid medications.
Multimodal regimens were
developed to reduce opioid
consumption and associated
adverse effects.
Qualitative Literature review A growing body of evidence supports
multimodal analgesia in spine surgery.
Methods include the use of preemptive
analgesia, NSAIDs, the neuromodulatory
agents gabapentin and pregabalin,
acetaminophen and extended-action local
anesthesia. The development of a standard
approach to multimodal analgesia in spine
surgery requires extensive assessment of
the literature.
Multimodal analgesia
could decrease the
opioid use during the
preoperative period
Leung, P., Macdonald,
E., Stanbrook, M.,
Dhalla, I., & Juurlink,
D. (2017). A 1980
Letter on the Risk of
Opioid Addiction. The
New England Journal of
Medicine., 376(22),
2194–2195.

A one-paragraph letter that
was published in the Journal
in 1980 was widely invoked
in support of this claim,
even though no evidence
was provided by the
correspondents. A
bibliometric analysis of this
correspondence from its
publication until March 30,
2017 was performed to
assess its effect,
Quantitative Retrospective The authors found that a five-sentence
letter published in the Journal in 1980 was
heavily and uncritically cited as evidence
that addiction was rare with long-term
opioid therapy. We believe that this
citation pattern contributed to the North
American opioid crisis by helping to
shape a narrative that allayed
prescribers’ concerns about the risk of
addiction associated with long-term
opioid therapy
Noncritical citation of
publications could
have substantial
negative effects.
44

Loftus, Randy W et
al(2010).
“Intraoperative
Ketamine Reduces
Perioperative Opiate
Consumption in
Opiate-Dependent
Patients with Chronic
Back Pain Undergoing
Back Surgery.”
Anesthesiology.113.3
639–646.

Intravenous ketamine on
induction of anesthesia and
a continuous infusion was
begun on induction and
terminated at wound closure
for the patients undergoing
major lumbar spine surgery
Quantitative Randomized,
prospective,
double-blinded
and placebo-
controlled trial

Intraoperative ketamine reduces opiate
consumption in the 48-h postoperative
period in opiate-dependent patients with
chronic pain. Ketamine may also reduce
opioid consumption and pain intensity
throughout the postoperative period in this
patient population.
Intraoperative
ketamine could
reduce opiate
consumption in the
postoperative period.
Maher, D., Chen, L., &
Mao, J. (2017).
Intravenous Ketamine
Infusions for
Neuropathic Pain
Management: A
Promising Therapy in
Need of Optimization.
Anesthesia & Analgesia,
124(2), 661–674.

Because there are many
widely divergent ketamine
infusion protocols described
in the literature, the
variation in these protocols
presents a challenge for
direct comparison of one
protocol with another and in
discerning an optimal
protocol.
Qualitative Literature
review
On the basis of the available evidence, a
successful ketamine infusion protocol for
the treatment of chronic neuropathic pain
would include several components: (1)
applying the longest possible infusion
duration that is logistically feasible using
multiple outpatient clinic visits if
necessary; (2) using a dose of ketamine
between 0.1 and 0.5 mg/kg/h to avoid
excessive sedation in the majority of
patients; and (3) utilizing adjunct
medications such as midazolam to
decrease the incidence of psychomimetic
side effects and possibly improve the
degree of pain relief. All infusions should
be done in a monitored setting.
Standard protocols
are essential for
effective use of
ketamine.
45

Moussavi, S., Chatterji,
S., Verdes, E., Tandon,
A., Patel, V., & Ustun,
B. (2007). Depression,
chronic diseases, and
decrements in health:
results from the World
Health Surveys. The
Lancet., 370(9590),
851–858.
Depression is an important
public-health problem and
one of the leading causes of
disease burden worldwide.
The WHO World Health
Survey (WHS) studied
adults aged 18 years and
older to obtain data for
health, health-related
outcomes and their
determinants. Prevalence of
depression in respondents
based on ICD-10 criteria
was estimated.
Quantitative Retrospective An average of between 9.3% and 23.0%
of participants with one or more chronic
physical disease had comorbid depression.
This result was significantly higher than
the likelihood of having depression in the
absence of a chronic physical disease.
After adjustment for socioeconomic
factors and health conditions, depression
had the largest effect on worsening mean
health scores compared with the other
chronic conditions.
Depression is a
common comorbidity
in patients with
chronic disease.
Niesters, M., Martini,
C., & Dahan, A. (2014).
Ketamine for chronic
pain: risks and benefits.
British Journal of
Clinical Pharmacology
BJCP., 77(2), 357–367

The anesthetic ketamine is
used to treat various chronic
pain syndromes, especially
those that have a
neuropathic component.
Qualitative Descriptive Low dose ketamine produces strong
analgesia in neuropathic pain states,
presumably by inhibition of the N-methyl-
D-aspartate receptor although other
mechanisms are possibly involved,
including enhancement of descending
inhibition and anti-inflammatory effects at
central sites. Close monitoring of patients
receiving ketamine is mandatory,
particularly aimed at CNS, hemodynamic,
renal and hepatic symptoms as well as
abuse.

Low dose ketamine
produces strong
analgesia in
neuropathic pain
states
46

Nielsen, R.,
Fomsgaard, J., Siegel,
H., Martusevicius, R.,
Nikolajsen, L., Dahl, J.,
& Mathiesen, O. (2017).
Intraoperative ketamine
reduces immediate
postoperative opioid
consumption after spinal
fusion surgery in
chronic pain patients
with opioid dependency:
a randomized, blinded
trial. Pain., 158(3),
463–470.

The study evaluated the
effect of intraoperative
ketamine on immediate
postoperative opioid
consumption in chronic pain
patients with opioid
dependency undergoing
lumbar spinal fusion surgery
Quantitative prospective,
randomized,
blinded tri
Patient-controlled analgesia IV morphine
consumption 0 to 24 hours postoperatively
was significantly reduced in the ketamine
group compared with the placebo group
Intraoperative
ketamine could
decrease immediate
postoperative opioid
consumption in
chronic pain patients
with opioid
dependency
Porter J, Jick H.
Addiction rare in
patients treated with
narcotics. (1980.). New
England Journal of
Medicine., 302(2).

Patient records were
assessed to determine the
incidence of narcotic
addiction in 39,946
hospitalized medical
patients

who were
monitored consecutively.
Quantitative Retrospective
study
The authors concluded that despite
widespread use of narcotic drugs in
hospitals, the development of addiction is
rare in medical patients with no history of
addiction.

47

Rosero, E., & Joshi, G.
(2014). Preemptive,
preventive, multimodal
analgesia: what do they
really mean? Plastic &
Reconstructive Surgery,
134(4 Suppl 2), 85S–
93S.

To improve postoperative
pain management, several
concepts have been
developed, including
preemptive analgesia,
preventive analgesia and
multimodal analgesia.
Qualitative Multimodal analgesia consists of the
administration of 2 or more drugs that act
by different mechanisms for providing
analgesia. These drugs may be
administered via the same route or by
different routes. Thus, the aim of
multimodal analgesia is to improve pain
relief while reducing opioid requirements
and opioid-related adverse effects.
Multimodal analgesia
could decrease
postoperative pain
and opioid use.
Rudd, R., Aleshire, N.,
Zibbell, J., & Gladden,
R. (2016). Increases in
Drug and Opioid
Overdose Deaths--
United States, 2000-
2014. Morbidity and
Mortality Weekly Report
MMWR /, 64(50-51),
1378–1382.

CDC analyzed recent
multiple cause-of-death
mortality data to examine
current trends and
characteristics of drug
overdose deaths, including
the types of opioids
associated with drug
overdose deaths.
Quantitative Retrospective
study
Between 2013 and 2014, the age-adjusted
rate of death involving methadone
remained unchanged; however, the age-
adjusted rate of death involving natural
and semisynthetic opioid pain relievers,
heroin, and synthetic opioids, other than
methadone (e.g., fentanyl) increased 9%,
26% and 80%, respectively. These
findings indicate that the opioid overdose
epidemic is worsening. There is a need for
continued action to prevent opioid abuse,
dependence, and death, improve treatment
capacity for opioid use disorders and
reduce the supply of illicit opioids,
particularly heroin and illicit fentanyl.
The opioid overdose
epidemic is
worsening. There is a
need for continued
action to prevent
opioid abuse,
dependence and death
48

Rudd, R., Seth, P.,
David, F., & Scholl, L.
(2016). Increases in
Drug and Opioid-
Involved
Overdose Deaths -
United States, 2010-
2015. Morbidity and
Mortality Weekly Report
MMWR /, 65(50-51),
1445–1452.

In an effort to target
prevention strategies to
address the rapidly changing
epidemic, CDC examined
overall drug overdose death
rates during 2010-2015 and
opioid overdose death rates
during 2014-2015 by
subcategories
(natural/semisynthetic
opioids, methadone, heroin
and synthetic opioids other
than methadone).

Quantitative Retrospective
study
Rates of deaths involving other opioids,
specifically heroin and synthetic opioids
other than methadone (likely driven
primarily by illicitly manufactured
fentanyl), increased sharply overall and
across many states. A multifaceted,
collaborative public health and law
enforcement approach is urgently needed.
A multifaceted,
approach is required
to address opioid
crisis.
Sabatowski, R.,
Schäfer, D., Kasper, S.,
Brunsch, H., &
Radbruch, L. (2004).
Pain treatment: a
historical overview.
Current Pharmaceutical
Design., 10(7), 701–
716.

This article gives a brief
review on pain, pain beliefs
and pain management from
early magicodemonic and
magico religious ideas and
procedures to more empiric-
scientific models

Qualitative Modern analgesics were synthesized and
new invasive procedures were approved
having a major impact on pain
management strategies. However, older
traditional beliefs and attitudes have not
been replaced completely and have
survived to some degree in modern
patients.

49

Schwenk, E., &
Mariano, E. (2018).
Designing the ideal
perioperative pain
management plan starts
with multimodal
analgesia. The Korean
Society of
Anesthesiologists, 71(5),
345–352

Evidence today supports
the routine use of
multimodal analgesia in the
perioperative period to
eliminate the over-reliance
on opioids for pain control
and to reduce opioid-related
adverse events.

Qualitative A multimodal analgesic protocol should
be surgery-specific, functioning more like
a checklist than a recipe, with options to
tailor to the individual patient. Elements of
this protocol may include opioids, non-
opioid systemic analgesics like
acetaminophen, non-steroidal anti-
inflammatory drugs, gabapentinoids,
ketamine and local anesthetics
administered by infiltration, regional
block, or the intravenous route.
Multimodal analgesia
in the perioperative
period could decrease
opioid use for pain
control and reduce
opioid-related adverse
events.

Schwenk, E., Viscusi,
E., Buvanendran, A.,
Hurley, R., Wasan, A.,
Narouze, S., Bhatia, A.,
Davis, F., Hooten, W.,
Cohen, S. (2018).
Consensus Guidelines
on the Use of
Intravenous Ketamine
Infusions for Acute Pain
Management From the
American Society of
Regional Anesthesia
and Pain Medicine, the
American Academy of
Pain Medicine, and the
American Society of
Anesthesiologists.
Regional Anesthesia
and Pain Medicine,
43(5), 456–466.
The widespread variability
in patient selection,
treatment parameters and
monitoring indicates a need
for the creation of
consensus guidelines for the
use of ketamine infusion.
Qualitative Guideline Consensus guidelines were prepared in
the following areas: indications,
contraindications for acute pain and
whether they differ from those for chronic
pain, the evidence for the use of ketamine
as an adjunct to opioid-based therapy, the
evidence supporting patient-controlled
ketamine analgesia, the use of
nonparenteral forms of ketamine and the
subanesthetic dosage range and whether
the evidence supports those dosages for
acute pain. The group was able to reach
consensus on the answers to all questions.

50

Shea, R., Brooks, J.,
Dayhoff, N., & Keck, J.
(2002). Pain intensity
and postoperative
pulmonary
complications among
the elderly after
abdominal surgery.
Heart & Lung the
Journal of Acute and
Critical Care., 31(6),
440–449.

To determine whether
postoperative pain intensity
differs between elderly
abdominal surgery patients
in whom postoperative
pulmonary complications
(PPC) develop and those in
whom they do not.
Quantitative Secondary
analysis of data
from a
prospective study
Pain is a factor that contributes to the
development of postoperative pulmonary
complications (PPC) among the elderly
population after abdominal surgery.
Therefore, nursing interventions of pain
assessment and management, deep
breathing and ambulation may influence
the incidence of this outcome.
Postoperative pain
control is essential, as
pain is a factor that
contributes to the
development of
postoperative
pulmonary
complications (PPC)
Singh, J., Fedgchin,
M., Daly, E., De Boer,
P., Cooper, K., Lim, P.,
Pinter, C., Murrough,
J., Sanacora, G.,
Shelton, R., Kurian, B.,
Winokur, A., Fava, M.,
Manji, H., Drevets, W.,
Van Nueten, L. (2016).
A Double-Blind,
Randomized, Placebo-
Controlled, Dose-
Frequency Study of
Intravenous Ketamine
in Patients With
Treatment-Resistant
Depression. The
American Journal of
The study evaluated the
efficacy of twice- and
thrice-weekly intravenous
administration of ketamine
in sustaining initial
antidepressant effects in
patients with treatment-
resistant depression.
Quantitative Double-blind,
randomized,
Twice-weekly and thrice-weekly
administration of ketamine at 0.5 mg/kg
similarly maintained antidepressant
efficacy over 15 days.
Ketamine is effective
in patients with
treatment-resistant
depression.
51

Psychiatry., 173(8),
816–826.

Tan, W., Yu, J.,
Feaman, S.,
McAllister, J., Kahan,
L., Quasebarth, M.,
Blatnik, J., Eagon, J.,
Awad, M., Brunt, L.
(2018). Opioid
Medication Use in the
Surgical Patient: An
Assessment of
Prescribing Patterns
and Use. Journal of the
American College of
Surgeons., 227(2),
203–211.

Comparing postoperative
opioid prescriptions with
patient use. During the first
14 post-discharge days and
at their first postoperative
clinic visit, patients
recorded pain scores and
number of opioid pills
taken.

Quantitative prospective
cohort study
Patients were prescribed a median of 150
morphine milligram equivalents (MME) .
However, by their first postoperative visit,
they had only taken a median 30 MME.
Postoperative patients might consume less
than half of the opioid pills they are
prescribed.

52

Urban, M., Ya Deau,
J., Wukovits, B., &
Lipnitsky, J. (2008).
Ketamine as an adjunct
to postoperative pain
management in opioid
tolerant patients after
spinal fusions: a
prospective
randomized trial. HSS
Journal : the
Musculoskeletal
Journal of Hospital for
Special Surgery., 4(1),
62–65.

The use of ketamine as an
adjunct to acute pain
management in narcotic
tolerant patients after spinal
fusion was assessed.
Quantitative prospective
randomized
study
Patients who received 0.2 mg/kg on
induction of general anesthesia and then 2
mcg kg(-1) hour(-1) for the next 24 hours
had significantly less pain during their
first postoperative hour in the PACU and
continued to have less pain during the first
postoperative day at rest and with physical
therapy.
Ketamine is effective
in pain control for
narcotic tolerant
patients after spine
surgery.
Warfield, C., & Kahn,
C. (1995). Acute pain
management. Programs
in U.S. hospitals and
experiences and
attitudes among U.S.
adults. Anesthesiology.,
83(5), 1090–1094.

The status of acute pain
management in U.S.
hospitals and attitudes of
adults in the U.S. toward
postoperative pain
management were assessed
through survey.
Qualitative Survey Fifty-seven percent of those who had
surgery cited concern about pain after
surgery as their primary fear experienced
before surgery. Seventy-seven percent of
adults reported pain after surgery, with
80% of these experiencing moderate to
extreme pain.

Pain is a frequent
issue after surgery
and needs to be
addressed.
53

Zakine, J., Samarcq,
D., Lorne, E.,
Moubarak, M.,
Montravers, P.,
Beloucif, S., &
Dupont, H. (2008).
Postoperative
ketamine
administration
decreases morphine
consumption in major
abdominal surgery: a
prospective,
randomized, double
blind, controlled
study. Anesthesia
Analgesia, 106(6),
1856–1861.

Ketamine decreases
postoperative morphine
consumption, but its optimal
dosing and duration of
administration remains
unclear. In this study, the
effects of ketamine
administration on morphine
consumption limited to the
intraoperative period, or
continued for 48 h
postoperatively were
compared
Quantitative Randomized
double-blind
Cumulative morphine consumption 24 h
after surgery was significantly lower in the
group receiving intraoperative and
postoperative ketamine for the first 48 h
after surgery.
Ketamine decreases
postoperative
morphine
consumption
Zhou, Y., Peng, Y.,
Fang, J., Sun, W.,
Zhang, G., Zhen, L.,
Wang, G., Han, R.
(2018). Effect of low-
dose ketamine on
Perioperative
depressive Symptoms
in patients undergoing
Intracranial tumor
resection (PASSION):
study protocol for a
randomized controlled
Aims to determine whether
ketamine could improve the
depressive symptoms of
perioperative patients
undergoing supratentorial
brain tumor resection. It will
also examine the safety of
administering ketamine as
an intraoperative anti-
depressant.

Quantitative Single-center,
randomized,
placebo-
controlled and
double blind
trial.
The primary outcome is the rate of
response to treating PDS at 3
postoperative days, which is defined as a
relative reduction of more than 50% from
the baseline10-item MADRS score. The
primary outcome as well as the other
psychological assessment will be
evaluated by the trained and qualified
psychiatrist who is blinded to the
grouping.
Ketamine could
improve the
depressive symptoms
of perioperative
patients
54

trial. Trials,
19(1).

Abstract (if available)

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Asset Metadata

Creator Sedigh, Touraj (author)

Core Title Perioperative ketamine as a strategy to decrease opioid use in anesthesia care for opioid dependent patients with chronic pain: an extensive literature review with practice recommendations

School Keck School of Medicine

Degree Doctor of Nurse Anesthesia Practice

Degree Program Nurse Anesthesiology

Publication Date 05/21/2020

Defense Date 05/21/2020

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag anesthesiologist,effectiveness,efficacy,ketamine,multimodal analgesia,N-methyl-D-aspartate receptor,non-opioid analgesics,nurse anesthetist,OAI-PMH Harvest,opioid,opioid epidemic,opioid-free pain management,opioid-use disorder,perioperative medicine,Safety,subanesthetic

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Griffis, Charles (committee chair), Blu Bamgbose, Elizabeth (committee member), Darna, Jeffrey (committee member)

Creator Email touraj.sedigh@gmail.com,tsedigh@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-313470

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Legacy Identifier etd-SedighTour-8547.pdf

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Document Type Capstone project

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Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

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