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Sponsored by Integrity Continuing Education, Inc.
Supported by an educational grant from Mylan.
The Role of Short-acting Opioids in Current Anesthesia Practice
Bernadette Henrichs, PhD, CRNA
Professor & DirectorNurse 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
3Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.
4
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:
*May have deleterious effects in critically ill and pediatric patients; Mandel, J. E. J Clin Anesth. 2014;26(1 Suppl):S1-7.
SEVO/DES • Isolated cases of hepatotoxicity
N2O
• Nausea and vomiting• Diffusional hypoxemia • Pulmonary bleb rupture • Pneumothorax expansion• Inactivation of vitamin B12
*
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
5
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.
IV Agents for the Induction and Maintenance of General Anesthesia
6
IV AGENT POTENTIAL ADVANTAGES POTENTIAL DISADVANTAGES
Propofol
– Good recovery profile– Short half-life– Low PONV incidence
– Bradycardia– Hypotension– Burning sensation
Etomidate
– Preferred if vasodilation and cardiac depression are contraindicated
– Adrenal insufficiency– Higher PONV incidence– Burning sensation
Ketamine
– 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.
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
7
*P<.05Gozdemir 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.
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
8Shepherd J. Health Technology Assessment 2013;17:34.
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
9Shepherd J. Health Technology Assessment. 2013;17:34.
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
10Lendvay V, et al. J Anesthe Clinic Res. 2010;1:103.Cove ME, Pinsky MR. Best Pract Res Clin Anaesthesiol. 2012;26(4):453-462.
Rationale for the Use of Short-acting Opioids in General
Anesthesia
11
Opioid Receptors and Responseto Stimulation
12
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
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.
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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 functionX
Desirable Characteristics of the µ-Opioids
Remifentanil Hydrolysis by Non-specific Esterases in the Blood and Tissues
N-C-CH2-CH3
C-O-CH3
Remifentanil
CH3-O-C-CH2-CH2-N
O
O
O
C-O-CH3
N-C-CH2-CH3
H-O-C-CH2-CH2-N
O
O
O
GR90291
N-C-CH2-CH3
C-O-CH3H-N
O
O
GR94219
Nonsp
ecifi
c
Este
rase
s>95% Major Metabolite
(Inactive)
Egan TD. Clin Pharmacokinet. 1995;29(2):80-94.
Pharmacokinetic Properties of µ-Opioids
*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.
Pharmacokinetics Alfentanil Fentanyl Remifentanil Sufentanil
Onset: blood-effect siteequilibration, mean
0.96 min 6.6 min 1.6 min 6.2 min
Organ-independentelimination
No No Yes No
Nonspecific esterasemetabolism
No No Yes No
Offset: context-sensitivehalf-time, mean*
50-55 min† >100 min† 3-6 min 30 min†
17
Practical Considerations:Rapid Onset
ADVANTAGES
• Rapid response to titration and bolus
• Control of anesthetic depth
• Hemodynamic stability
• Predictable plasma & receptor level
DISADVANTAGES
• Increased risk for:
– Bradycardia
– Hypotension
– Chest wall rigidity
– Apnea
Opioid Infusion Front-end Kinetics: Quick to Steady State
19Egan TD (in Miller & Pardo). Elsevier;2011.
Pro
port
ion
of S
tead
y-S
tate
Ce
(%)
Infusion Duration (min)
Morphine
Sufentanil
Fentanyl
Alfentanil
Remifentanil100
80
60
40
20
00 100 200 300 400 500 600
Infusion begins at time zero
Opioid Infusion Back-end Kinetics: Rapid Offset After Infusion
20Egan TD (in Miller & Pardo). Elsevier;2011.
Tim
e to
50%
Dec
rem
ent
in C
e (%
)
Infusion Duration (min)
Morphine
Sufentanil
Fentanyl
Alfentanil
Remifentanil
400
350
300
250
200
150
100
50
0
0 100 200 30 400 500 600
0 60 120 180 240 300 360 420 4800.1
1
10
100
Mean Concentration Over Time With Short-acting Opioids
Time (min)
Mea
n C
on
cen
trat
ion
(n
g/m
L)
(n=5)0.5 mcg/kg/min
(n=6)0.05 mcg/kg/min
Discontinuation of infusion
21
Alfentanil
Remifentanil
ULTIVA [Mylan Inc.] Available at: http://www.ultiva.com/files/Ultiva-Prescribing-Info.pdf
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
Ausems ME, et al. Anesthesiology. 1986;65:362-373.
Plasma Alfentanil (ng/mL)
100
50
00 200 400 600 800 1000
Intubation
Skin Incision
Skin Closure
Probability of No Response (%) (n=37)
Opioid Pharmacodynamic Variability
Ausems ME, et al. Anesthesiology. 1988;68:851-861.
Probability of No Response to Surgical Incision (%)
Plasma Alfentanil (ng/mL)
100
50
0200 400 600
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
28
*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.
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
32
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
36
Short-acting Opioid Improves Time to Orientation Compared With N2O
37
Pro
po
rtio
n N
ot
Ori
ente
d
Time (min)
Infusion of remifentanil 0.085 µg/kg/min compared with
66% N2O
1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20 25
Remifentanil
Nitrous oxide
Mathews DM, et al. Anesth Analg. 2008;106:101-108.
38
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.
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
46Deiner S. Semin Cardiothorac Vasc Anesth. 2010;14(1):51-53.
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
Propofol Emergence Data
49
DIPRIVAN (propofol) injection, emulsion [APP Pharmaceuticals, LLC]. Available at:http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee0c3437-614d-4631-a061-257f5f60c70b.
Pla
sma
Pro
pofo
l Con
cent
ratio
n(m
cg/m
L)
1.00
0.75
0.50
0.25
0.00
Minutes After End of Infusion
0 20 40 60 80
Target plasma concentration Recovery after:10-day infusion10-hour infusion1-hour infusion
Awakening
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 51Vadivelu N, et al. Yale J Biol Med. 2010;83(1):11-25.
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
54
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.
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
55
Thank you!