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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

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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†

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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

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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

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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 

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*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

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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

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.

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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

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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

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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

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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

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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

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Thank you!