The Role of Short-acting Opioids in
Current Anesthesia Practice
Sponsored by Integrity Continuing Education, Inc.
Supported by an educational grant from Mylan.
Bernadette Henrichs, PhD, CRNA
Professor & Director
Nurse Anesthesia Program
Goldfarb School of Nursing
Barnes-Jewish College
St. Louis, Missouri
2
Overview of General Anesthesia
• Goals of general anesthesia
– Rapid induction and maintenance of optimal operating conditions
– Reduction of side effects
– Rapid emergence and recovery
• A combination of agents is used to induce and maintain
general anesthesia in current practice
– IV hypnotics and sedatives
– Volatile inhalational agents
– Opioids
– Muscle relaxants
Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.
3
Volatile Inhalation Agents for the
Maintenance of General Anesthesia
• Common agents include sevoflurane (SEVO), desflurane
(DES), and nitrous oxide (N2O)
• N2O with SEVO or DES provides fast, reliable recovery and
lowers risk of myocardial depression
• Associated adverse events:
SEVO/DES
N 2O
*May
• Isolated cases of hepatotoxicity
•
•
•
•
•
Nausea and vomiting
Diffusional hypoxemia
Pulmonary bleb rupture
Pneumothorax expansion
Inactivation of vitamin B12*
have deleterious effects in critically ill and pediatric patients; Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.
4
Total Intravenous Anesthesia
(TIVA)
• An alternative to the use of volatile agents for
maintenance of anesthesia
• Anesthesia is produced entirely using IV anesthetics
administered by target-controlled infusion or manual
injection
• Short-acting opioids play a central role (though not
always required for minimally stimulating procedures)
• Short-acting agents enable rapid recovery even after
long infusions
Cole CD, et al. Neurosurgery. 2007;61(5 Suppl 2):369-377. DeConde AS, et al. Int Forum Allergy Rhinol. 2013;3(10):848-854. Lerman J, et al.
Paediatr Anaesth. 2009;19(5):521-534. Mandel JE. J Clin Anesth. 2014;26(1):S1-S7. Mani V, et al. Paediatr Anaesth. 2010;20(3):211-222.
5
IV Agents for the Induction and
Maintenance of General Anesthesia
IV AGENT
Propofol
Etomidate
Ketamine
POTENTIAL ADVANTAGES
POTENTIAL DISADVANTAGES
– Good recovery profile
– Short half-life
– Low PONV incidence
– Bradycardia
– Hypotension
– Burning sensation
– Preferred if vasodilation and
cardiac depression are
contraindicated
– Adrenal insufficiency
– Higher PONV incidence
– Burning sensation
– Preferred for reactive
airway patients
(bronchodilatory)
– Cardiovascular stimulation
– Hallucinations, vivid dreams,
delirium
– Benzodiazepines can improve
but may slow emergence and
recovery
Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.
6
Clinical Comparisons of Anesthesia
Techniques
• TIVA compared to inhalation anesthesia (IA) in vertebral
disk surgery:
– Shorter recovery times (spontaneous ventilation, extubation, eye
opening, and ability to give name and date of birth)*
– Less PONV
– Greater analgesic demand
• TIVA compared to IA in pediatric ENT surgery:
– Lower perioperative heart rate
– Less postoperative agitation
• TIVA and balanced volatile anesthesia in intracranial
surgery were found to be comparable
*P<.05
Gozdemir M, et al. Adv Ther. 2007;24(3):622-631. Grundmann U, et al. Acta Anaesthesiol Scand. 1998;42(7):845-850. Magni G, et
al. J Neurosurg Anesthesiol. 2005;17(3):134-138.
7
Monitoring of Vital Signs to Assess
Depth of Anesthesia
• Potential signs of intraoperative awareness/stress:
– Tachycardia (rapid heart rate)
– Hypertension
– Sweating
– Lacrimation (tear production)
– Movement/grimacing
– Tachypnea (rapid breathing)
• New technologies for monitoring (EEG, BIS)
– Helps to indicate the level of unconsciousness
– Does not guarantee against intraoperative awareness
Shepherd J. Health Technology Assessment 2013;17:34.
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Maintaining Appropriate Depth of
Anesthesia
• Excessive level of anesthesia
– Increases risk of postoperative nausea, vomiting, and
cognitive dysfunction
• Insufficient level of anesthesia
– Places patient at risk for intraoperative awareness
– Although relatively rare, intraoperative awareness can
cause depression, anxiety, and post-traumatic stress
disorder
Shepherd J. Health Technology Assessment. 2013;17:34.
9
Hemodynamic Stability During
Surgery
• Hemodynamic instability can result in complications
• Hemodynamic measures are important indicators of
the following:
– Sufficient cardiac output
– Adequate SV; Volume status
– Organ perfusion
– Adequacy of pain control
– Depth of anesthesia
Lendvay V, et al. J Anesthe Clinic Res. 2010;1:103.
Cove ME, Pinsky MR. Best Pract Res Clin Anaesthesiol. 2012;26(4):453-462.
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Rationale for the Use of
Short-acting Opioids in
General Anesthesia
11
Opioid Receptors and Response
to Stimulation
Receptor
Response
Mu-1
•
Supraspinal analgesia
Mu-2
•
•
•
•
Depression of ventilation
Cardiovascular effects
Physical dependence
Euphoria
Delta
•
Modulate mu receptors
Kappa
•
•
•
Spinal analgesia
Sedation
Miosis
Sigma
•
•
Dysphoria
Hypertonia
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Advantages of the Use of Opioids
for General Anesthesia
• Analgesia
– Blunts neuroendocrine activation
• Hemodynamic stability
– No direct myocardial depression
– Blunts catecholamine response to noxious stimuli
• Decreased stress response
– Attenuates stress response during surgery
• Decreased need for hypnotic anesthetics
– Less propofol needed
Brown EN., et al. Annu Rev Neurosci. 2011;34:601-628. Fukuda K (2010). Opioids. In RD Miller et al., eds., Miller's
Anesthesia, 7th ed., pp. 2519-2700. Wilmore DW. Ann Surg. 2002;236(5):643-648.
Specific Benefits Associated with
the Use of Short-acting Opioids
• Minimal effects of drug accumulation
• Predictable and rapid onset and offset
• Rapid patient response to titration allows close
management of intraoperative status
• Potential for faster recovery time and reduced PONV
• Benefits are not generally affected by gender, age,
weight, or renal/hepatic function
Wilhelm W, et al. Crit Care. 2008;12 (Suppl 3):S5. Egan TD. Curr Opin Anaesthesiol. 2000;13(4):449-455. Egan TD,
et al. Anesthesiology. 1996;84(4):821-833. Minto CF, et al. Anesthesiology. 1997;86(1):10-23.
Desirable Characteristics of the
µ-Opioids
Characteristic
Alfentanil
Fentanyl
Remifentanil
Sufentanil
µ-Opioid receptor
selectivity
X
X
X
X
No histamine release
X
X
X
X
Rapid response to titration
X
Rapid, predictable offset of
opioid effects (5-10 min)
X
Elimination independent of
renal or hepatic function
X
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Remifentanil Hydrolysis by Non-specific
Esterases in the Blood and Tissues
Remifentanil
O
CH3-O-C-CH2-CH2N
O
C-OCH3
O
N-C-CH2CH3
>95% Major Metabolite
O
(Inactive)
O
C-O-CH3
O
H-O-C-CH2-CH2N
H-N
N-C-CH2CH3
O
N-C-CH2CH3
GR90291
Egan TD. Clin Pharmacokinet. 1995;29(2):80-94.
C-OCH3
O
GR94219
Pharmacokinetic Properties of
µ-Opioids
Pharmacokinetics
Alfentanil
Fentanyl
Remifentanil
Sufentanil
Onset: blood-effect site
equilibration, mean
0.96 min
6.6 min
1.6 min
6.2 min
Organ-independent
elimination
No
No
Yes
No
Nonspecific esterase
metabolism
No
No
Yes
No
50-55 min†
>100 min†
3-6 min
30 min†
Offset: context-sensitive
half-time, mean*
*The time required for drug concentrations in blood or at effect site to decrease by 50%. Based on a 3-hour infusion.
† Increases with increasing infusion duration due to accumulation.
Data derived from manufacturers’ labeling and Egan TD, et al. Anesthesiology. 1993;79:881-892. Egan TD, et al.
Anesthesiology. 1996;84:821-833. Scott JC, et al. Anesthesiology. 1991;74:34-42.
17
Practical Considerations:
Rapid Onset
ADVANTAGES
• Rapid response to
titration and bolus
DISADVANTAGES
• Increased risk for:
– Bradycardia
• Control of anesthetic
depth
– Hypotension
• Hemodynamic
stability
– Apnea
• Predictable plasma &
receptor level
– Chest wall rigidity
Proportion of Steady-State Ce (%)
Opioid Infusion Front-end Kinetics:
Quick to Steady State
100
Remifentanil
80
Morphine
Alfentanil
Sufentanil
60
Fentanyl
40
20
Infusion begins at time zero
0
0
100
200
300
400
500
600
Infusion Duration (min)
Egan TD (in Miller & Pardo). Elsevier;2011.
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Time to 50% Decrement in Ce (%)
Opioid Infusion Back-end Kinetics:
Rapid Offset After Infusion
400
Fentanyl
350
Morphine
300
250
200
150
100
Alfentanil
50
Sufentanil Remifentanil
0
0
100
200
30
400
500
600
Infusion Duration (min)
Egan TD (in Miller & Pardo). Elsevier;2011.
20
Mean Concentration Over Time With
Short-acting Opioids
Discontinuation
of infusion
Mean Concentration (ng/mL)
100
(n=5)
0.5 mcg/kg/min
Alfentanil
Remifentanil
10
1
(n=6)
0.05 mcg/kg/min
0.1
0
60
120
180
240
300
360
420
480
Time (min)
ULTIVA [Mylan Inc.] Available at: http://www.ultiva.com/files/Ultiva-Prescribing-Info.pdf
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Practical Considerations:
Rapid Offset
ADVANTAGES
• Rapid response to
titration
• Predictable
emergence
• High-dose opioid
technique without
need for post-op
ventilation
• Ideal for TIVA
DISADVANTAGES
• No residual analgesia
– Hemodynamic
instability
Procedure-associated Variability in
Opioid Pharmacodynamics
Probability of No Response (%) (n=37)
100
Intubation
50
Skin Incision
Skin Closure
0
0
200
400
600
Plasma Alfentanil (ng/mL)
Ausems ME, et al. Anesthesiology. 1986;65:362-373.
800
1000
Opioid Pharmacodynamic
Variability
Probability of No Response to Surgical Incision (%)
100
50
0
200
400
Plasma Alfentanil (ng/mL)
Ausems ME, et al. Anesthesiology. 1988;68:851-861.
600
Risks Associated with the Use of
Opioids in General Anesthesia
• Respiratory depression
• Bradycardia
• Chest wall/laryngeal muscle rigidity
• PONV
• Pruritus
• Delayed emergence
• Dependency
• Potential hyperalgesia
Bowdle TA. Drug Saf. 1998;19(3):173-189. Egan TD. Clin Pharmacokinet. 1995;29(2):80-94. Fletcher D, et al.
Br J Anaesth. 2014;112(6):991-1004. Komatsu R, et al. Anaesthesia. 2007;62(12):1266-1280.
Choosing an Anesthetic
Technique
26
Discussion Questions: Technique
Considerations
• How do you determine which technique is most
appropriate for a given patient?
• What are the primary concerns associated with
each technique?
Impact of Inhalation vs Intravenous
(IV) Administration of Agents
• Less PONV and greater patient satisfaction has been
observed with the following:
– IV induction compared to inhalation induction*
– TIVA compared to an inhalation component
• Emergence and discharge for outpatients is essentially
identical
• Inhalational anesthesia may be economically
advantageous over TIVA
*Both followed by inhalation maintenance. Kumar, G., et al. Anaesthesia. 2014. [Epub ahead of print]
Joshi GP. Anesthesiol Clin North Am. 2003;21(2):263-272.
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The Anesthesia Technique You Use
Should Be Based on Your Goals
• Balanced anesthesia with opioid and volatile agent
– Safe
– Practiced for decades
• TIVA
– Safe
– Relative newcomer to the OR
– Outpatient > inpatient
– May impact patient satisfaction
OR, Operating Room
Goals of Neuroanesthesia
• Hemodynamic stability without vasodilators
• Improved ability to rapidly change anesthetic depth
• Rapid recovery with early ability to assess
neurologic function
• Improved SSEP monitoring with TIVA
SSEP, somatosensory evoked potential.
Goals of ENT
• Hemodynamic stability without vasodilators
• Decreased bleeding, improved operative conditions
during nasal/sinus surgery or tonsillectomy
• Rapid awakening, rapid ability to protect airway,
rapid recovery
Case Study #1
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Case Study #1: 17-year-old Female
• Procedure: Septoplasty and sinus endoscopy
• History:
– Significant history of nasal passage obstruction and
difficulty breathing
– History of chronic sinusitis beginning at age 3
• Surgical history:
– Tonsillectomy at age 7 related to obstructive sleep
apnea (OSA); complicated by prolonged paralysis to
succinylcholine
Case Study #1: 17-year-old Female
(cont’d)
• Comorbidities:
– Asthma
– Obesity
– OSA with nasal obstruction
• Current medications:
– Saline nasal irrigation qd
– Albuterol prn
• Allergies:
– Penicillin
– No other known allergies
Case Study #1: Consideration of
Patient Characteristics
• How do the patient’s characteristics influence your
approach to formulating a plan for anesthesia?
– OSA
– Obesity
– Asthma
– Atypical pseudocholinesterase deficiency
• Specific concerns with regard to this type of surgical
procedure: May be stimulating at times but no incision
to close at end of case
Emergence & Recovery
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Short-acting Opioid Improves Time
to Orientation Compared With N2O
1.0
Proportion Not Oriented
Remifentanil
0.8
Nitrous oxide
0.6
Infusion of remifentanil
0.085 µg/kg/min
compared with
66% N2O
0.4
0.2
0.0
0
5
10
15
20
25
Time (min)
Mathews DM, et al. Anesth Analg. 2008;106:101-108.
37
Comparison of the Short-acting Opioids:
Impact on Patient Recovery
• Similar PONV is observed with fentanyl, remifentanil,
alfentanil, and sufentanil
• Use of remifentanil vs other short-acting opioids is
associated with the following:
– Faster postoperative recovery
– Less respiratory depression
– Higher postoperative analgesic requirements
– More shivering
Reviewed in: Komatsu R, et al. Anaesthesia. 2007;62(12):1266-1280.
38
Case Study #2
39
Case Study #2: 73-year-old Male
• Procedure: Right carotid endarterectomy
• Comorbid conditions:
–
–
–
–
Coronary artery disease
Type 1 diabetes
Hypertension
Peripheral vascular disease
• Surgical history:
– Left femoral popliteal bypass at age 71
– Stent inserted at age 68
Case Study #2: 73-year-old Male
(cont’d)
• Current medications:
– Lisonopril 20 mg qd
– Insulin glargine 0.2 units/kg/day
• Renal evaluation:
– Renal insufficiency determined by glomerular filtration rate
(GFR) of 61 mls/min/1.73m2
• Vascular evaluation:
– 90% occlusion of right carotid
– 50% occlusion of left carotid
• Allergies:
– No known allergies
Case Study #2: Questions for
Consideration
• What considerations should be given for:
– Regional vs general anesthesia?
– Tracheal intubation vs laryngeal mask airway (LMA) device?
• What monitoring would you employ intraoperatively?
• Consider the patient’s medical history (HTN) and renal
impairment in the anesthetic plan
• Important to consider quick emergence to assess neurological
function
Case Study #3
43
Case Study #3: 42-year-old Female
• Procedure:
– Multi-level laminectomy with lumbar fusion
– Intraoperative neurophysiologic monitoring (sensory evoked
potentials, motor evoked potentials)
• Surgical history:
– Previous back surgery to repair herniated disc 3 years ago
• Medical history:
– Current smoker
• Current medications:
– Naproxen sodium 500 mg bid (discontinued 10 days ago)
Case Study #3: Questions for
Consideration
• What considerations are given for TIVA vs mixed
anesthesia in this patient?
• Consider intraoperative monitoring of this patient
• Consider surgeon request for possible intraoperative
wake up for neurologic examination
• Consider patient’s history of chronic pain medication
Intraoperative Neurophysiological
Monitoring
• Main modalities:
– Somatosensory evoked potentials (SSEPs)
– Motor evoked potentials (MEPs)
– Electromyography (EMGs); transcranial monitoring
• While both inhaled and intravenous agents blunt
signal attainment, depression is greater with inhaled
agents
Deiner S. Semin Cardiothorac Vasc Anesth. 2010;14(1):51-53.
46
Case Study #3: Anesthetic Plan
• TIVA with propofol and fast-acting opioid infusion
• If intraoperative wake up is necessary, it will be
possible
• Consider patient’s history of chronic pain medication
– Give pain medicine before emergence
– IV Acetaminophen; IV NSAID; longer-acting narcotic
Emergence and Recovery:
Considerations
• Goal is to prepare for and have a smooth transition
to postoperative analgesia
• Early planning is essential with an agent with a rapid
offset of action (within 5-10 minutes)
– Non-cumulative effects are beneficial during surgery, but a
disadvantage postoperatively in terms of pain control
– Need to be prepared and address pain
• Risks for obstruction and for pulmonary aspiration are
also important to consider
Plasma Propofol Concentration
(mcg/mL)
Propofol Emergence Data
Target plasma concentration
Recovery after:
10-day infusion
10-hour infusion
1-hour infusion
Awakening
1.00
0.75
0.50
0.25
0.00
0
20
40
60
80
Minutes After End of Infusion
DIPRIVAN (propofol) injection, emulsion [APP Pharmaceuticals, LLC]. Available at:
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee0c3437-614d-4631-a061-257f5f60c70b.
49
Postoperative Management:
Analgesia
50
Postoperative Pain
• Postoperative pain is a significant cause of delayed
discharge after ambulatory surgery
• Good pain control is important for prevention of negative
outcomes:
– Tachycardia
– Hypertension
– Myocardial ischemia
– Decreased alveolar ventilation
– Poor wound healing
• Pain control must be individualized
Vadivelu N, et al. Yale J Biol Med. 2010;83(1):11-25.
51
Options for Postoperative Pain
Management
• Choice of analgesia should be a multimodal
approach:
– Nonsteroidal agent administered IV or IM
– IV acetaminophen
– Major nerve block
– Local anesthetic wound infiltration
– Long-acting opioids administered 20 to 30 minutes before
discontinuation of certain short-acting opioids
– Consider epidural administration of an opioid and/or local
anesthetic
IM, intramuscular
Opioids in Postoperative Analgesia
• Give opioids prior to emergence as needed
– IV Acetaminophen if not given at induction
– Ketorolac 30 mg IV ~30 min or Caldolor IV
– Dilaudid 0.2-2.0 mg IV ~ 20-30 min
– MSO4 0.1 to 0.2 mg/kg IV ~20 to 30 min
– Fentanyl 1 to 1.5 u/kg IV ~5 min
• Dose epidural if epidural placed
• Surgeon: Infiltrate with long-acting local anesthetic
• Consider continuing remifentanil 0.05 to 0.1
mcg/kg/min in PACU
Considerations for Special
Populations
• Age; Elderly more sensitive to narcotics
• Body mass effects; Obese more sensitive to
narcotics
• Comorbid conditions
• Current medications
Strom C, et al. Anaesthesia. 2014;69(S1):35-44. Lerman J. Eur J Anaesthesiol. 2013;30(11):645-650. Ingrande J, et al. Br J Anaesth.
2010;105 (S1):16-23. Hachenberg T, et al. Curr Opin Anaesthesiol. 2014;27(4):394-402.Licker M, et al. Int J Chron Obstruct Pulmon Dis.
2007;2(4):493-515.
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Summary
• Opioids used in anesthesia play a critical role in minimizing
surgical pain and the associated adverse effects on patient
outcomes
• The pharmacokinetic profiles of newer short-acting opioids are
characterized by lower drug accumulation and rapid, predictable
onset and offset
• The resulting rapid response to titration of short-acting opioids
enables close intraoperative management of hemodynamics,
patient stress response, and depth of anesthesia
• With appropriate use, short-acting opioids have the potential to
improve recovery and overall patient experience and satisfaction
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Thank you!