AANA Journal Course

Evidence-Based Use of Nonopioid Analgesics

Michael J. Kremer, PhD, CRNA, FNAP, FAAN
Charles A. Griffis, PhD, CRNA

Analgesia is a necessary component of any anesthetic anesthetics, nonsteroidal anti-inflammatory medica-

technique, and can be achieved with local anesthetics,
opioid and nonopioid analgesics, and inhaled anes-
thetic agents. Risks and benefits are associated with
each of the agents and techniques described here,
including local anesthetic systemic toxicity, respiratory
depression, nausea, and urinary retention. Implemen-
tation of Enhanced Recovery After Surgery (ERAS)
protocols, use of preemptive analgesia techniques,
and the national opioid crisis are fostering increased
utilization of nonopioid analgesics, including local
tions, intravenous acetaminophen, neuromodulatory
agents such as gabapentin, corticosteroids, centrally
acting α2 agonists, and ketamine. Certified Registered
Nurse Anesthetists optimize the safety and quality
of care they provide through use of evidence-based
practice, including the drugs they select, order, and
administer, such as opioid and nonopioid analgesics,
when providing anesthesia care.
Keywords: Analgesia, nonopioids, opioids.

Objectives through direct inhibition of ascending transmission of

At the completion of this course the reader should be nociception from the dorsal horn of the spinal cord and
able to: activation of descending pain control pathways from the
1. Describe the risks and benefits of opioid analgesics. midbrain via the rostral ventromedial medulla to the
2. 
Review nonopioid analgesics in terms of mecha- spinal cord and dorsal horn. Opioids can have sedative
nisms of action, doses, risks, and benefits. and euphoric effects that vary according to the involved
3. 
Discuss the impact of Enhanced Recovery After agent, with µ agonists such as morphine producing
Surgery protocols on pain management. greater sedation and euphoria and κ agonists like butor-
4. Identify the impact of the opioid crisis on selecting, phanol producing dysphoria.3
ordering, and administering opioid agonists. In healthy patients, when opioids are included in an
5. List the mechanisms of action for psychotropic and anesthetic regimen, bradycardia resulting from medullary
anticonvulsant agents used as analgesic adjuncts. vagal stimulation occurs, with little effect on blood pres-
sure. Dose-dependent peripheral vasodilation is associated
Introduction with opioids, but myocardial contractility, baroreceptor
Opioids suppress pain through their actions in the brain, function, and autonomic responsiveness are not affected.3
spinal cord, and peripheral nervous system. Appropriate Cough suppression results from the depressant effects of
titration and monitoring of opioids attenuate many of the opiates on the cough center in the medulla. In the context
adverse effects of these drugs. Opioids are central to the of anesthesia and critical care, opioids help patients toler-
analgesic aspect of anesthesia, notably when total intrave- ate breathing devices and mechanical ventilation.2
nous (IV) anesthesia is used.1 The common acute clinical
effects of opioid agonists are discussed in this section and Benefits of Opioid Analgesics
in Table 1. Common chronic effects of opioids include The term balanced anesthesia was first used in 1926,
tolerance, physical dependence, and constipation.2 meaning that a combination of anesthetic agents and
Opioids have effects on the major body systems, techniques could be used to produce the components
including the central nervous system (CNS), where of anesthesia, including analgesia, amnesia, muscle re-
varying degrees of analgesia, sedation, and euphoria are laxation, and ablation of autonomic reflexes. Use of an
associated with these drugs. Opioids produce analgesia opioid as a component of balanced anesthesia attenuates
The AANA Journal Course is published in each issue of the AANA Journal. Each article includes objectives for the reader and sources
for additional reading. A 10-question open-book exam for each course is published on www.AANALearn.com and will remain live
on the site for a period of 3 years. One continuing education (CE) credit can be earned by successfully completing the examination
and evaluation. Each exam is priced at $35 for members and $21 for students but can be taken at no cost by using one of the
six free CEs available annually to AANA members as a benefit of membership. For details, go to www.AANALearn.com. This
educational activity is being presented with the understanding that any conflict of interest has been reported by the author(s). Also,
there is no mention of off-label use for drugs or products.

www.aana.com/aanajournalonline AANA Journal  August 2018  Vol. 86, No. 4 321

pain and anxiety, decreases hemodynamic responses to
airway instrumentation, lowers minimal alveolar con-
centration requirements for inhaled anesthetics, and
provides postoperative analgesia. The synergy between
opioids and induction agents reduces the dose require-
ment for induction agents.4-6
Lowenstein et al7 demonstrated in 1969 that opioid-
based anesthesia using morphine, 0.5 to 3 mg/kg, could
be used safely in patients with minimal cardiac reserve
undergoing open heart surgery. Hemodynamic stabil-
ity can now be achieved with myriad drugs and anes-
thetic regimens, with opioids, including fentanyl and its
analogs, remaining key components of anesthesia care.4
Alfentanil and remifentanil allow rapid titration because
of the 1- to 2-minute onset to peak effect times, and nar-
cotic antagonists are seldom needed after remifentanil
administration.1
Opioids are associated with prevention of myocardial
ischemia through δ and κ receptor agonism, enhancing
myocardial resistance to oxidative and ischemic stressors.
Mitochondrial adenosine triphosphate (ATP)-regulated
potassium channels (KATP) may be pivotal in this signal-
ing pathway.8
Drawbacks of Opioid Analgesics
Morphine, even in the large doses described earlier, is
unlikely to cause direct myocardial depression. However,
changing from a supine to a standing position in a patient
medicated with morphine can result in orthostatic hy-
potension and syncope related to altered sympathetic
nervous system compensatory responses due to venous
pooling.9 Decreased blood pressure due to bradycardia
and histamine release are known morphine side effects
than can be attenuated by not administering greater than
5 mg/min of morphine, having the patient maintain the
supine position, and providing adequate hydration.10
Opioid agonists produce respiratory depression that is
dose-related through µ2 receptor agonism resulting in de-
pression of brainstem ventilation centers.11 Respiratory
depression related to opioids is rapid and persists for
several hours, as evidenced by decreased ventilatory re-
sponses to carbon dioxide. Death due to opioid overdose
typically results from ventilatory depression.12
Sedation typically precedes analgesia with morphine.
A suggested interval of 5 to 7 minutes between morphine
doses permits evaluation of the clinical effects of this
drug. The sedation associated with morphine should not
be construed as adequate analgesia.12
Opioids provoke nausea and vomiting through stimu-
lation of the chemoreceptor trigger zone in the medullary
area postrema. Vestibular components may also con-
tribute to postoperative nausea and vomiting, since this
occurs more frequently in ambulatory surgical patients.
Postoperative nausea and vomiting are more frequent
when opioids are included in anesthetic management.13
322 AANA Journal  August 2018  Vol. 86, No. 4 www.aana.com/aanajournalonline
Acute effect Chronic effect
Analgesia Tolerance
Respiratory depression Physical dependence
Sedation Constipation
Euphoria
Dysphoria
Vasodilation
Bradycardia
Cough suppression
Miosis
Nausea and vomiting
Skeletal muscle rigidity
Smooth-muscle spasm
Constipation
Urinary retention
Biliary spasm
Pruritis, rash
Antishivering (meperidine)
Histamine release
Hormonal effects
Table 1. Common Clinical Effects of Opioid Agonists
Used by permission from Nagelhout JJ. Opioid agonists and
antagonists. In: Nagelhout J, Elisha S, eds. Nurse Anesthesia. 6th
ed. St Louis, MO: Elsevier; 2018:128-139.
When large doses of fentanyl and its analogs are ad-
ministered rapidly, generalized skeletal muscle rigidity
that interferes with ventilation can result. This increased
skeletal muscle tone is likely related to decreased striatal
γ-aminobutyric acid (GABA) release and increased do-
pamine release and can be offset by muscle relaxants or
opioid antagonists.14 This phenomenon is described as
being uncommon in one article, with the authors noting
that “this complication is better described in pediatric
patients” with anesthetic doses of fentanyl and other
opiates. Chest wall rigidity can occur with analgesic
doses of fentanyl and its analogs. Management includes
ventilatory support and reversal with naloxone or admin-
istration of a neuromuscular blocking agent.15
Opioids can result in itching, rash, and a feeling of
warmth in the face, arms, and upper aspect of the chest.
This occurs with histamine as well as nonhistamine-re-
leasing drugs and occurs more frequently with neuraxial
opioids, likely because of activation of central µ recep-
tors.16 Narcotic antagonists like naloxone and naltrexone
may be used to treat pruritis at the expense of decreased
analgesia. Nalbuphine, droperidol, antihistamines, and
ondansetron can also be used to treat pruritis associated
with opioids.17
Opioids decrease gastric motility and peristalsis, pro-
longing gastric emptying time and reducing secretions
throughout the gastrointestinal (GI) tract. This produc-
es opioid-induced constipation and postoperative ileus.
Opioid-induced constipation does not lessen over the
Drug classification Mechanism Example
MOR agonists Stimulate central and peripheral MOR, Morphine, hydromorphone, fentanyl
produce analgesia
Local anesthetics Block sodium channels peripherally; Lidocaine, bupivacaine, ropivacaine
depress CNS
Anticonvulsants (adjuvant drug) Block spinal cord voltage-dependent Pregabalin
calcium channels
Antianxiety (adjuvant drug) Inhibit reuptake of norepinephrine and Amitriptyline
serotonin at descending inhibitory fiber
synapses
NMDA antagonists Block NMDA receptors Ketamine
Alpha-2 agonists Stimulate spinal cord α2 receptors Dexmedetomidine, clonidine
COX inhibitors/NSAIDs Block COX-1 and/or COX-2 enzymes, Ibuprofen, ketorolac, naproxen
inhibiting PGE production
Corticosteroids Block phospholipase A2 Dexamethasone

Table 2. Analgesic Drug Classes and Mechanisms of Effect

Abbreviations: CNS, central nervous system; COX, cyclooxygenase; MOR, μ (mu) opioid receptors; NMDA, N-methyl-d-aspartate;
NSAIDs, nonsteroidal anti-inflammatory drugs; PGE, prostaglandin E.

course of long-term opioid treatment. Peripherally acting
µ opioid receptor antagonists, including methylnaltrex-
one, naloxegol, and alvimopan improve bowel symptoms
without compromising opioid analgesic effects. The poten-
tial side effects of these drugs include abdominal pain.18
Dose-dependent increases in biliary duct pressure and
sphincter of Oddi tone are produced by opioid receptor-
mediated mechanisms. Opioids also increase urinary
sphincter tone.2
Although opioids blunt the surgical stress response,
these drugs also have immunosuppressant effects.
Opioids inhibit natural killer cell function and stimu-
late cancer cell proliferation because of their effects on
angiogenesis and tumor cell signaling pathways.19 Use
of nonopioid analgesics may help offset these risks in
scenarios involving immunocompromise or cancer.
Nonopioid Mechanisms of Analgesia
The Certified Registered Nurse Anesthetist (CRNA) has a
robust arsenal of nonopioid analgesic drugs from which
to choose, depending on the individual patient’s history
and needs (Table 2). Acetaminophen is a well-character-
ized nonopioid analgesic drug, often chosen because of
its benign effect on gastric mucosa and platelet function,
although it is known to have no ameliorating effect on
inflammation.20 The exact mechanism of action of ac-
etaminophen remains unclear, although some investiga-
tions have suggested the drug has a weak effect on cyclo-
oxygenase 1 (COX-1) and COX-2 gene expression. The
IV form of acetaminophen, marketed as Ofirmev, is given
over 30 minutes at a dose of 1,000 mg every 6 hours for
children and adults weighing more than 50 kg, and 15
mg/kg every 6 hours for children 2 to 12 years of age
and adults and adolescents weighing less than 50 kg.21
Clinical investigation has shown the parenteral form of
acetaminophen to have a powerful analgesic opioid-spar-
ing effect, presumably due, at least in part, to the lack of a
first-pass liver effect.22 The side effects of acetaminophen
can include allergic reaction and liver toxicity. Indeed,
it is important to inform the patient and postoperative
care team members of acetaminophen administration, to
prevent overdose.
Ketamine is a dissociative anesthetic agent with pro-
found analgesic effects due to noncompetitive inhibi-
tion of N-methyl-d-aspartate receptors in the CNS.23
Ketamine use for nonopioid analgesia has been revived
in recent years because of the drug’s efficacy and lack
of opioid-related side effects, and its utility when used
for opioid-dependent chronic pain patients.24 Ketamine
doses for analgesia vary depending on the patient and
clinical situation, and in one clinical investigation of
opioid-dependent patients undergoing back surgery,
patients received 0.5 mg/kg of ketamine on induction,
followed by an infusion of 10 μg/kg/min started before
incision and terminated on skin closure.24 Patients who
received ketamine required 37% less morphine and re-
ported less pain at 6-week postoperative follow-up. Side
effects include increased oral secretions, tachycardia and
hypertension, vivid and unpleasant dreams, and increas-
es in intracranial pressure.
Dexamethasone is a glucocorticoid steroid drug,
which is a fluorinated derivative of prednisolone.23 Used
traditionally for its anti-inflammatory effects on such
conditions as airway inflammation and cerebral edema,
this glucocorticoid drug is being increasingly used for its
systemic analgesic effect23,25 and for its ability to prolong
peripheral neural blockade when administered parenter-
ally or as a component of the local anesthetic solution.26
Doses vary widely depending on the intended effect,
route of administration, and clinical situation, with 8 mg
intravenously having been reported to have a systemic
analgesic effect, and a similar dose combined with local

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anesthetics prolonging sciatic nerve block. However, it is
important to note that dexamethasone is not approved
by the US Food and Drug Administration for perineural
administration.25,26 The mechanism of effect is unclear,
but the drug inhibits phospholipase A2, thus decreasing
pain-causing prostaglandin production, and locally ad-
ministered glucocorticoid compounds have been found
to inhibit nociceptive C-fibers.27 Although many side
effects are associated with longer-term administration,
acute side effects seem limited to increases in plasma
glucose levels and to unpleasant perineal sensations in
awake patients following rapid IV administration.
Dexmedetomidine is a highly selective centrally acting
α2 receptor agonist with analgesic and sedative effects.
When administered at a rate of 0.2 to 0.7 µg/kg/min, the
drug blunts central sympathetic responses, and produces
CNS depression. Dexmedetomidine lessens opioid-relat-
ed muscle rigidity, decreases postoperative shivering, and
produces minimal respiratory depression. Use of dexme-
detomidine as an analgesic adjunct decreases morphine
consumption.28
Low-dose clonidine is an effective analgesic adjunct
in neuraxial as well as peripheral nerve blocks. Systemic
low-dose IV clonidine is a useful analgesic adjunct for
postoperative pain.29
Local anesthetics that are administered systemically,
including IV lidocaine, oral mexiletine, and oral tocainide
have benefits in some chronic pain states. Systemically
administered local anesthetics have been used to treat
of postoperative pain,30 burn pain,31 and cancer pain.32
There is evidence that systemically administered local
anesthetics attenuate pain associated with some chronic
pain states, including IV lidocaine infusions for neuro-
pathic pain treatment.33
The potential side effects of systemically administered
local anesthetics include lightheadedness, dizziness, tin-
nitus, vertigo, blurred vision, and changes in taste, with
seizures occurring at higher blood levels. The cardiovas-
cular side effects of local anesthetics include hypoten-
sion, bradycardia, and cardiac arrest. Investigators have
found that the primary side effect experienced by 6% of
patients who were treated with IV lidocaine for neuro-
pathic pain was transient dizziness.34 Given the potential
side effects of systemically administered local anesthetics,
these agents are not practical for routine clinical use as
systemic analgesics.
Topical 5% lidocaine has been used to successfully
treat postherpetic neuralgia and painful neuropathies as
well as postsurgical pain.35 Some formulations of topical
diclofenac and ketoprofen provide effective analgesia
for sprains and strains but are less effective than topical
lidocaine in treating chronic pain such as that associated
with osteoarthritis. Adverse effects observed with topical
local anesthetics typically involve mild skin reactions.36
Postoperative pain from peripheral surgeries are
324 AANA Journal  August 2018  Vol. 86, No. 4 www.aana.com/aanajournalonline
treated very effectively with long-acting local anesthet-
ics such as bupivacaine and ropivacaine when used
in peripheral nerve blocks.37 It is common practice in
outpatient surgical settings for surgeons to infiltrate ap-
propriate wound edges with long-acting local anesthet-
ics and for nurse anesthetists to administer long-acting
regional blocks for extremity surgeries. Both approaches
decrease opioid requirements, helping avoid opioid-asso-
ciated side effects. Similarly efficacious is the use of local
anesthetics to provide postoperative analgesia through
performing transverse abdominis plane blocks for mida-
bdominal and lower abdominal procedures.38
Capsaicin, a major component of chili peppers, is sold
over the counter for temporary relief of pain related to
arthritis, myalgias, arthralgias, and neuralgias. This com-
pound is a transient receptor potential vanilloid (TRPV1)
cation channel agonist.39 In inflammatory conditions,
TRPV1 receptor sensitivity is increased; TRVP2 receptors
are found on unmyelinated peripheral C-fiber endings.
Activation of the TRPV receptor results in the release of
high-intensity impulses and substance P, which causes
burning. Ongoing release of substance P as a result of
capsaicin exposure results in decreased C-fiber activa-
tion.40 Topical capsaicin lacks efficacy with treatment of
musculoskeletal and neuropathic pain.41
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
widely used in acute and chronic pain management.42
Parenteral preparations have increased the use of NSAIDs
for efficacious, opioid-sparing, acute perioperative pain
management. The mechanism of effect is the block of
pain-causing prostaglandin production, through inhibi-
tion of COX-1 and/or COX-2, which are key enzymes
in the arachidonic acid pathway. Ketorolac (marketed
as Toradol) is administered as a one-time 60-mg intra-
muscular dose or 30-mg IV dose every 6 hours to adults
with no contraindications for a maximum of 5 days.23
Parenteral ibuprofen (marketed as Caldolor) is admin-
istered in a varying dose depending on age: 6 months to
12 years, 10 mg/kg IV over 10 minutes up to a maximum
single dose of 400 mg every 4 to 6 hours as needed; ages
12 to 17 years, 400 mg IV every 4 to 6 hours as needed;
adults receive 400 to 800 mg IV over 30 minutes every
6 hours as needed.43 There are numerous oral prepara-
tions of NSAIDs, some of which are specific inhibitors of
COX-2. All NSAIDs share similar adverse effects related
to inhibition and disruption of the normal physiologic
effects of the COX enzyme system. These effects include
the following: platelet inhibition, which may cause
bleeding; GI ulceration and bleeding; decreases in renal
perfusion; exacerbations of hypertension; heart failure
and fluid retention; and increased incidence of serious
cardiovascular events, including myocardial infarction
and stroke. The drugs are contraindicated for the treat-
ment of cardiac surgical patients and for laboring women
(due to labor effects related to prostaglandin inhibition).
The NSAIDs may enhance bleeding when given with
anticoagulants or antiplatelet drugs, may decrease the
efficacy of angiotensin-converting enzyme inhibitor an-
tihypertensive drugs, may decrease diuretic effects, and
increase serum digoxin concentrations.43,44
A wide variety of psychotropic medications are used in
managing chronic pain, and increasingly acute pain with
limited evidence of efficacy, and a brief review of selected
examples follows. These medications include antidepres-
sants such as amitriptyline, desipramine, imipramine, and
nortriptyline. The suggested mechanism of effect is de-
creased reuptake of the neurotransmitters norepinephrine
and serotonin in descending inhibitory pain-modulating
pathways. Major side effects include sedation; altered
cardiac conduction; and anticholinergic phenomena, such
as dry mouth and difficulty urinating. Anticonvulsant
drugs such as carbamazepine are also used in chronic pain
management, blocking pain impulses by sodium channel
blockade, but use is limited by side effects including se-
dation, ataxia, blood dyscrasias, nausea, and vomiting.
Newer anticonvulsants such as gabapentin are also used,
with a less severe side effect profile. Onset of effect is slow
and variable (may take weeks), and dosing varies widely
depending on patient and clinical factors.45
The Opioid Crisis and Opioid Prescriptions
The Centers for Disease Control and Prevention notes
that the United States “is in the midst of an opioid over-
dose epidemic.”46 Prescription opioids as well as heroin
killed more than 33,000 people in 2015, the highest
recorded number of such fatalities. Prescription opioids
are involved in almost half of opioid overdose deaths.46
Suggested steps to improve opioid prescription pat-
terns, enhance addiction treatment, and limit access to
illegal opioids include the following:
• Improve opioid prescribing to limit opioid expo-
sure, prevent abuse, and stop addiction.
• Expand access to medication-assisted treatment, an
evidence-based treatment program, for people dealing
with opioid addiction.
• Increase access to and use of naloxone for first re-
sponders and family members.
• Use of state prescription drug monitoring pro-
grams, to provide information needed for safe prescrib-
ing practices.46
The judicious use of opioids in anesthesia care, com-
bined with the integration of nonopioid adjunctive drugs,
may help ameliorate concerns related to the amount of peri-
operative opioids administered. Enhanced Recovery After
Surgery protocols judiciously balance the use of anesthetic
agents and techniques to achieve optimal patient outcomes.
Impact of Enhanced Recovery After Surgery
Protocols on Pain Management
Enhanced Recovery After Surgery protocols are lists of
www.aana.com/aanajournalonline AANA Journal
multimodal, multidisciplinary actions recommended to
anesthesia and surgery teams with the goal of decreasing
time spent as an inpatient following major surgery. Such
approaches are growing swiftly in popularity since being
introduced in recent years because of their cost-effective-
ness in reducing the economic burden on patients and
institutions, and are supported through research, program
development, and institutional implementation by such
nonprofit national organizations as the American Society
of Enhanced Recovery (ASER) and the ERAS Society, an
international professional organization. Typically, ERAS
perioperative approaches contain some combination of
the following elements: minimally invasive surgical ap-
proaches that avoid large incisions; carbohydrate drinks 2
hours before incision; careful fluid titration to avoid over-
hydration; avoidance of nasogastric tubes, wound drains,
and early removal if indicated; and early mobilization.
From its inception, ERAS has incorporated anesthetic
technique and pain management approaches as central to
achieving the goal of early ambulation and discharge.47
Regional anesthesia is employed, which may involve
neuraxial approaches such as combined spinal and epi-
dural, or epidural anesthesia with catheter placement
for postoperative analgesia. In general, the thoracic
spine level of epidural catheter insertion depends on the
location of the planned surgery, with an upper T-spine
placement (approximately T6-T7) for thoracic surgery;
midthoracic placement for thoraco-abdominal and upper
abdominal procedures (approximately T7-T9); and
lower T-spine placement for lower abdominal surger-
ies. Typically, postoperative analgesia is maintained
for approximately 48 hours with infusions of dilute
local anesthetics (usually bupivacaine or ropivacaine) in
combination with a low concentration of a hydrophilic
or lipophilic opioid at several milliliters per hour, with
boluses for breakthrough pain, and titrated to patient
comfort. Benefits include early ambulation and effective
pulmonary hygiene, and reduced incidence of postopera-
tive ileus. Side effects, although rare, can be bothersome
and require an educated staff to prevent, detect, and
treat. Local anesthetics can cause sympathetic, sensory,
and motor block, and epidural opioids can cause urinary
retention, pruritis, nausea, and vomiting.48 In general,
epidural analgesia is used effectively in ERAS protocols
for major urologic, orthopedic, and other surgeries.
Conclusion
In the past, opioids were regarded as the first-line and
most effective and safest treatment of painful injuries,
syndromes, and surgeries. Now that the limitations and
side effects of opioid drug therapy have been recognized
and with the onset of the devastating opioid overdose ep-
idemic, it is clear that a paradigm shift in the treatment of
pain is imperative. Clinical scientists have begun making
progress in presenting anesthesia providers with an ever-
 August 2018  Vol. 86, No. 4 325
increasing range of pain treatment options, including
nonopioid analgesic drugs and neural block procedures.
As the treatment of pain continues to evolve and increas-
ingly includes nonopioid approaches, it is essential that
CRNAs remain abreast of these developments so that
we may continue to offer the safest and most efficacious
treatment modalities to our patients.
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NEWSBULLETIN
www.aana.com/aanajournalonline AANA Journal
AUTHORS
Michael J. Kremer, PhD, CRNA, FNAP, FAAN, is a professor at Rush Uni-
versity College of Nursing and codirector, Rush Center for Clinical Skills
and Simulation, Rush University, Chicago, Illinois. Email: Mike_J_Kre-
mer@rush.edu.
Charles A. Griffis, PhD, CRNA, is assistant clinical professor, UCLA
School of Nursing Faculty, USC Doctor of Nurse Anesthesia Practice Pro-
gram, Los Angeles, California
DISCLOSURES
The authors have declared no financial relationships with any commercial
entity related to the content of this article. The authors did discuss off-
label use within the article.
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