1. The Use of Ultra-Short
Opioids in Anesthesia
Mark D. Antoszyk, CRNA, BS

3. Pharmacokinetics of Remifentanil: Overview
Rapid offset of opioid effects (within 5-10 min)
Rapid blood-effect site equilibration half-time
(approximately 1.6 min) leading to rapid onset of action
Rapid response to titration
Nonspecific esterase metabolism
Elimination unaffected by sex, weight,
or renal/hepatic function
Egan TD, et al. Anesthesiology. 1996;84:821-833.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

4. Remifentanil Metabolism
Hydrolyzed by nonspecific esterases in the blood and
tissues: organ-independent elimination
Rapid clearance without accumulation regardless of
dosage level or duration of infusion
Metabolism not altered in patients with
pseudocholinesterase deficiency
Clearance is not altered by concomitant thiopental,
isoflurane, propofol, or temazepam during anesthesia
In vitro studies of hydrolysis not inhibited by
atracurium, mivacurium, esmolol, echothiophate,
neostigmine, physostigmine, or midazolam
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

5. Context-sensitive Half-time of -Opioid Agonists
Adapted with permission from Egan TD, et al. Anesthesiology. 1993;79:881-892.
Duration of Infusion (min)
100
75
50
25
0
0 100 200 300 400 500 600
SimulationofTimeto50%Decrease
inBloodConcentration(min)
Fentanyl
Alfentanil
Sufentanil
Remifentanil
Study A104.

6. Dosing Guidelines

7. Remifentanil Dosing Guidelines for
General Anesthesia
*An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.
Reduce starting dosage up to 50% in elderly (>65 y) patients.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].
Anesthesia Phase
(Adults)
Induction (through intubation)
Maintenance with
Nitrous oxide (66%)
Isoflurane (0.4-1.5 MAC)
Propofol (100-200 mcg/kg/min)
Continuous
IV Infusion
(mcg/kg/min)
Infusion Dose
Range
(mcg/kg/min)
Supplemental
IV Bolus Dose
(mcg/kg)
0.5-1*
0.4
0.25
0.25
0.1-2
0.05-2
0.05-2
1
1
1

8. Bolus Dose Equivalents
• Remifentanil 70 g (1 g/kg) 
• Fentanyl 225 g (3.2 g/kg)
• Alfentanil 1000 g (15 g/kg)
• Sufentanil 25 g (0.35 g/kg)
• Remifentanil 35 g (0.5 g/kg) 
• Fentanyl 100 g (1.5 g/kg)
• Alfentanil 500 g (7 g/kg)
• Sufentanil 12 g (0.2 g/kg)
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

9. Bolus vs 1 minute infusion
• True bolus peaks about
a minute earlier than a
“bolus” given over 1
minute
• Both will be associated
with a rapid onset of
drug effect
• Side effects will be
similar with both
0
2
4
6
0 2 4 6 8 10
Minutes
Remifentanilconcentration(ng/ml)
One minute infusion
True Bolus
Apnea
Ventilatory Depression
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

10. Induction: Bolus vs Infusion
• Concentrations
rapidly rise during
infusions.
• With infusions,
expect apnea and
rigidity within 2-3
minutes.
• Especially at a rate
of 1.0 g/kg/min
0
5
10
15
20
25
0 2 4 6 8 10
Minutes
Remifentanilconcentration(ng/ml)
1.0g/kg/min
1 g/kg bolus
Apnea
Ventilatory Depression
Rigidity
0.5g/kg/min
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

11. Maintenance Infusion Rates
• 1.0 g/kg/min
• Profound analgesia
• 0.5 g/kg/min
• Paralysis required
• 0.25 g/kg/min
• Ventilation required
• > 50% MAC reduction
• 0.1 g/kg/min
• Works well with nitrous
• May be satisfactory
for spontaneous
ventilation
0
5
10
15
20
25
30
0 10 20 30 40 50 60
Minutes
Remifentanilconcentration(ng/ml)
1.0g/kg/min
0.5g/kg/min
Respiratory depression
Apnea
Rigidity
0.25g/kg/min
0.1g/kg/min
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

12. Remifentanil Adverse Events: General Anesthesia*
Nausea
Vomiting
Adverse Event†
R
(n=921)
A/F
(n=466)
R
(n=281)
M
(n=98)
R
(n=929)
A/F
(n=466)
Hypotension
Muscle Rigidity
Bradycardia
Shivering
Fever
Respiratory
Depression
<1%
19%
<1%
11%‡
7%
<1%
<1%
<1%
0%
6%
<1%
8%
5%
0%
0%
0%
22%
0%
8%
2%
1%
5%
<1%
7%
15%
0%
5%
0%
3%
9%
0%
4%
36%
2%
16%
<1%
1%
5%
5%
2%
43%
2%
20%
<1%
1%
2%
2%
4%
Induction/
Maintenance
Postoperative
Analgesia
After
Discontinuation
*Not all doses of remifentanil were equipotent to the comparator opioid. Administration of remifentanil in
excess of the recommended doses (ie, >1 and up to 20 mcg/kg resulted in a higher incidence of some
adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%).
R = remifentanil; A/F = alfentanil/fentanyl; M = morphine. †Adverse events that occurred in  5% of patients
in general anesthesia studies. ‡Incidence of chest wall rigidity (5%) is included in muscle rigidity.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

13. Mac Dosing

14. Remifentanil Dosing Guidelines for MAC*
Method
(Adults) Timing
Remifentanil
Alone
Remifentanil +
Midazolam (2 mg)
Single IV
dose
90 sec before
local anesthetic
1 mcg/kg over
30-60 sec
0.5 mcg/kg over
30-60 sec
Continuous
IV infusion
Begin 5 min
before local
anesthetic
0.1 mcg/kg/min 0.05 mcg/kg/min
After local
anesthetic
0.05 mcg/kg/min
(range: 0.025-
0.2 mcg/kg/min)
0.025 mcg/kg/min
(range: 0.025-
0.2 mcg/kg/min)
*It is strongly recommended that supplemental oxygen be supplied to the patient
whenever remifentanil is administered as an analgesic component of monitored
anesthesia care.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

15. Infusion rates for MAC sedation
• 0.2 g/kg/min
• Apnea likely
• 0.1 g/kg/min
• Respiratory depression
• 0.05 g/kg/min
• Little likelihood of
respiratory depression
• 0.025 g/kg/min
• Few problems expected
• Modestly analgesic
0
2
4
6
8
10
0 10 20 30 40 50 60
Minutes
Remifentanilconcentration(ng/ml) 0.1 g/kg/min
0.025 g/kg/min
Respiratory depression
Apnea
Rigidity
0.05 g/kg/min
0.2 g/kg/min
Analgesia
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

17. Remifentanil Adverse Events: MAC
Nausea
Vomiting
Pruritus
Headache
Sweating
Shivering
Dizziness
Adverse Event*
44%
Remifentanil
(n=159)
Remifentanil +
Midazolam† (2 mg)
(n=103)
Propofol
(n=63)
22%
18%
18%
6%
5%
5%
18%
5%
16%
12%
0%
<1%
5%
32%
21%
0%
10%
2%
2%
2%
*Adverse events that occurred in  5% of patients. Administration of remifentanil in excess of the recommended
infusion rate (ie, starting doses >0.1 mcg/kg/min) resulted in higher incidence of some adverse events: nausea
(60%), apnea (8%), and muscle rigidity (5%).
†With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].
Hypotension
Bradycardia
Pain at IV site
4% 0% 10%
4% 0% 11%
1% 0% 17%

18. Special Populations

19. Special Populations
• Infants
• Very rapid clearance, even in newborns
• Half-life of 3-6 minutes
• 5 g/kg caused hypotension about 20% of patients
• Ross et al, Anesth Analg 2001 93:1393-401
• Not associated with increased post-op apnea
• Galinkin et al, Anesth Analg 2001 93:1387-92

20. Pharmacokinetics of Remifentanil in
Pediatric Patients
ULTIVA® (remifentanil hydrochloride) for injection [package insert].
Clearance
(mL/min/kg)
VDss
(mL/kg)Age
Neonate (<2 months)
Adolescent (13-16 y)
90.5±36.8
Mean (± SD)
57.2±21.1
452±144
223±30.6
Half-life same in neonates and adolescents
Clearance maintained at or above normal adult values
in patients aged 5 days to 17 years

21. Remifentanil Dosing Guidelines for
Special Patient Populations
Adjust dosing in
Elderly (>65 y): reduce initial dose by 50%
Obese (>30% above ideal body weight [IBW]): dose
to IBW
No dosage adjustment for
Children (1-12 y)*
Renal/hepatic dysfunction
Pseudocholinesterase deficiency
*Remifentanil has not been studied in pediatric patients for use in the
immediate postoperative period or for use as a component of MAC.
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

25. Age Effects on Remifentanil Pharmacokinetics
*EC50 = concentration required for 50% of maximum response; Ke0 = blood-brain
equilibration.
Data on file, Abbott Laboratories.
Parameter*
Age Group, y
Cl (mL/min/kg)
Vss (mL/kg)
EC50 (ng/mL)
Ke0 (per min)
30 50 75
39
312
17.3
1.0
35 (10%)
245 (21%)
13.5 (22%)
0.71 (29%)
29 (26%)
162 (48%)
8.7 (50%)
0.29 (71%)
Measure (% Change Relative
to 30-Year-Old Patient)

26. C50 decreases with age
• C50 is a measure of
brain sensitivity
• Decreased C50 means
increased sensitivity
• Decreased C50 with age
also reported for:
• fentanyl
• alfentanil
• sufentanil
Age (years)
20 40 60 80 100
0
10
20
30
C50(ng/ml)
Minto et al, Anesthesiology 86:10-23, 1997

27. Bolus doses should be reduced by 50%
in the elderly
• The reduction in bolus
dose is because of the
50% increase in
sensitivity in the elderly
• Adjusting the bolus for
age is at least as
important as adjusting it
for body weight 0
100
200
300
400
20 40 60 80
Age (years)
LBM
75kg
35kgBolus(g)
Minto et al, Anesthesiology 86:24-33, 1997

28. Infusion rates should be reduced by
2/3’s in the elderly
• The infusion rate is
decreased because of
increased sensitivity and
decreased clearance
• Adjusting the infusion
rate for age is more
important than adjusting
it for weight
20 40 60 80
0
10
20
30
40
50
60
Age (years)
LBM
75kg
35kg
InfusionRate(g/min)
Minto et al, Anesthesiology 86:24-33, 1997

29. Pharmacokinetics of Remifentanil in
Patients With Hepatic Impairment*
*Values shown are geometric mean (95% confidence interval); †low-dose infusion = 0.0125
mcg/kg/min for 1 hour followed by 0.025 mcg/kg/min for 3 hours; ‡high-dose infusion = 0.025
mcg/kg/min for 1 hour followed by 0.05 mcg/kg/min for 3 hours.
Adapted with permission from Dershwitz M, et al. Anesthesiology. 1996;84:812-820.
Clearance
(mL/min/kg)
Vd
(mL/kg)Treatment Group
T1/2
(min)
Hepatic
impairment (n=5)
Control (n=5)
33.3 (23.0-48.3) 272 (162-456)
33.0 (28.5-38.1) 205 (178-235)
5.7 (4.0-8.1)
4.3 (4.1-4.5)
High-dose group‡
Low-dose group†
Hepatic
impairment (n=5)
Control (n=5)
39.1 (33.2-46.0) 264 (196-356) 4.7 (3.7-5.9)
31.5 (23.8-41.6) 208 (112-384) 4.6 (2.8-7.4)
Study A211.

30. Pharmacokinetics of Remifentanil
in Patients With Renal Failure (<30 mL/min/1.73 m2)*
*Values shown are geometric mean (95% confidence interval); †low-dose infusion = 0.0125
mcg/kg/min for 1 hour followed by 0.025 mcg/kg/min for 3 hours; ‡high-dose infusion = 0.025
mcg/kg/min for 1 hour followed by 0.05 mcg/kg/min for 3 hours.
Adapted with permission from Hoke JF, et al. Anesthesiology. 1997;87:533-541.
Clearance
(mL/min/kg)
Vd
(mL/kg)Treatment Group
T1/2
(min)
Control (n=8) 33.2 (26.5-41.7) 191 (151-241) 4.0 (3.3-4.8)
Renal failure (n=9) 35.6 (31.7-40.0) 229 (211-249) 4.5 (3.9-5.1)
High-dose group‡
Low-dose group†
Renal failure (n=6) 35.1 (25.2-49.0) 282 (194-411) 5.6 (3.3-9.3)
Study A210.

31. Pharmacokinetics of Remifentanil in Obese
Patients
Open-label, single-dose, parallel, group study
12 obese (>80% IBW) and 12 lean (within 20% of
IBW) patients undergoing elective, noncardiac,
nonintracranial surgery
Patients received a 1-minute infusion of
remifentanil (7.5 to 10 mcg/kg/min)
Results
Absolute volumes and clearances are similar in
lean and obese patients
Dosing remifentanil based on total body weight
results in excessively high remifentanil levels
Egan TD, et al. Anesthesiology. 1998;89:562-573. Study A227.

32. Remifentanil: Safety Profile
Failure to adequately clear the IV tubing or
remove residual remifentanil HCl has been
associated with the appearance of respiratory
depression, apnea, and muscle rigidity upon the
administration of additional fluids or
medications through the same IV tubing

33. Remifentanil: Safety Profile (Cont’d)
Continuous infusions of remifentanil should be
administered only by an infusion device
In monitored anesthesia care, when patients
are breathing spontaneously, single boluses of
remifentanil should be administered over 30 to
60 seconds and should not be administered
simultaneously with a continuous infusion
IV bolus administration of remifentanil should
only be used during the maintenance of general
anesthesia

34. Remifentanil: Safety Profile (Cont’d)
Rapid clearance and lack of accumulation
result in rapid offset of analgesic effects
following discontinuation of remifentanil;
therefore, when postoperative pain is
anticipated, adequate postoperative analgesia
should be established before discontinuation
Remifentanil produces adverse events
characteristic of -opioids, such as respiratory
depression, bradycardia, hypotension, and
skeletal muscle rigidity

35. Setting up drug infusions
• Check out your infusion pump as thoroughly
as you check out your anesthesia machine.
• Is your drug dilution correct?
• Is the syringe adequately held?
• Is the syringe plunger properly held in the clamp?
• Are your infusion units correct?
• Is the weight correct (for calculator pumps)?
• Has the dead space been taken out of the line?
• Have the batteries been checked?
• Think of the check out as though you were
going to infuse sodium nitroprusside.
Steven L. Shafer, MD, Professor of Anesthesia, Stanford University

36. Setting up drug infusions
• Infuse as close to the IV catheter site as possible.
• Typical IV tubing contains 3-5 mls of dead space
between injection ports and catheter.

37. Positive Outcome Anesthesia with
Remifentanil
• Positive outcomes
• More stable intraoperative hemodynamics
• Faster emergence in OR
• Faster recovery in PACU
• Faster discharge
• Reduced N/V when combined with propofol
• Decrease MAC of Inhalation Agents
• Able to intubate without relaxants
• Remifentanil 3-4 g/kg + propofol 2-2.5 mg/kg
• Earlier studies used infusion rates of 0.25 – 1.0 g/kg, later studies
used 0.1 to 0.25 g/kg.

38. Unique Benefits
• Anesthesia maintained with high-dose remifentanil is
associated with rapid recovery.
• Within 5-10 minutes of turning off an infusion there is virtually no residual
remifentanil drug effect.
• The offset of opioid drug effect following turning off a remifentanil infusion
resembles the offset associated with giving titrated doses of naloxone to a
patient who has received fentanyl, alfentanil, or sufentanil.
• Even after “cardiac” type doses of remifentanil, patients will be awake within 5-
10 minutes of turning off an infusion

39. Unique Benefits
• High-dose opioid techniques with little risk of
post-operative ventilatory depression.
• Can do “cardiac” anesthetics on outpatients
• Every patient can have profound analgesia at critical junctures
(e.g. intubation, incision)

40. Potential Risks
Contains Glycine
• Contraindicated for use in epidurals and spinals
Rapid onset of Remifentanil
• Could lead to life threatening rigidity
• Usually seen with large bolus and rapid infusion
• Treatable with muscle relaxants and turning off infusion
Postoperative analgesics must be anticipated

41. Potential Risks
Interruptions in Remifentanil must be corrected quickly
• Have a second syringe prepared
• Have an alternative medication
• Be aware that within 3-5 minutes the patient will develop
pain
Titrate with caution
• Aggressive titration could lead to rigidity, apnea, or pain

42. Potential Risks
• Cannot be administered epidurally or
intrathecally.
• Contains glycine.

43. Unique Postoperative Analgesia Management
Within 5-10 min after remifentanil discontinuation,
no residual opioid activity will be present*
When postoperative pain is anticipated, ending an infusion of
remifentanil should be preceded by the establishment of adequate
postoperative analgesia*
Choices could include any 1 or a combination of the following,
depending on patient type or surgery
Nonsteroidal agents
Local anesthetic wound infiltration
Long-acting opioids
Epidural administration of an opioid and/or local anesthetic
*ULTIVA® (remifentanil hydrochloride) for injection [package insert].

44. Transition to postoperative analgesia
• Local Anesthesia
• Methadone 5-10 mg
• 45-60 minutes before the end of anesthesia
• Morphine 5-10 mg
• 15-30 minutes before the end of anesthesia
• Fentanyl 50-100 g
• 5-10 minutes before the end of anesthesia
• Continue remifentanil infusion.
• 7% incidence of severe ventilatory depression
 Bowdle et al, Anesth Analg 83:1292-7, 1996
 Probably reflects difficulty with infusion techniques

45. Remifentanil Summary
Precise control and rapid response
Rapid onset of action
Rapid titration provides rapid, precise control
of intraoperative stress responses
Predictable duration and offset of action
Rapid, predictable recovery (within 5-
10 minutes) due to organ-independent
elimination and noncumulative properties
ULTIVA® (remifentanil hydrochloride) for injection [package insert].

46. Remifentanil Summary (Cont’d)
Suitable for use in
Ambulatory and office-based procedures
Inpatient procedures
Patients who have renal or hepatic
impairment or are obese
Repeated or prolonged administration is not
associated with recurrent respiratory
depression (occurring >30 minutes after
discontinuation)
ULTIVA® (remifentanil hydrochloride) for injection [package insert].