Journal of Clinical Anesthesia (2014) 26, S1S7

Special Article

Considerations for the use of short-acting opioids in

general anesthesia
Jeff E. Mandel MD, MS (Assistant Professor)
Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania,
Philadelphia, PA 19104, USA
Received 4 November 2013; accepted 25 November 2013

Keywords:
General anesthesia;
Propofol;
Total intravenous
anesthesia;
Short-acting opioids;
Remifentanil;
Alfentanil;
Sufentanil

Abstract Anesthesiologists play a critical role in facilitating a positive perioperative experience

and early recovery for patients. Depending on the kind of procedure or surgery, a wide variety of
agents and techniques are currently available to anesthesiologists to administer safe and
efficacious anesthesia. Notably, the fast-track or ambulatory surgery environment requires the use
of agents that enable rapid induction, maintenance, and emergence combined with minimal
adverse effects. Short-acting opioids demonstrate a safe and rapid onset/offset of effect; that short
effect is both predictable and precise. It also ensures easier titration and reduced or rapidly
reversed side effects. Due to their distinct pharmacokinetic and pharmacodynamic properties, and,
in one case, rapid extra-hepatic clearance of remifentanil, these agents have several applications in
general anesthesia.
2014 Elsevier Inc. All rights reserved.

1. Introduction
General anesthesia is used to achieve a combination of
amnesia, analgesia, immobility, and sedation to provide
surgeons and proceduralists with optimal working conditions. While general anesthesia may be utilized with natural
airways during procedures that are minimally invasive, it
more frequently is associated with devices to maintain a
patent airway. In the current fast-track surgery environment,
general anesthesia provides a safe and comfortable experiFunding Sources: Mylan Specialty, LP, Canonsburg, PA, USA.
Correspondence: Jeff E. Mandel, MD, MS, Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, 3400
Spruce St., Philadelphia, PA 19104, USA. Phone: + 1 215-615-0553.
E-mail address: mandelj@uphs.upenn.edu.
0952-8180/$ see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jclinane.2013.11.003

ence that is coupled with reduced postoperative recovery

times and absence of overnight hospital stays [1]. However,
general anesthesia is associated with side effects such as
nausea, vomiting, shivering, sore throat, headache, malignant hyperthermia, and delayed return to normal mental
functioning [2]. Furthermore, general anesthesia may affect
cognitive function in the elderly [3,4]. The anesthesia
provider also monitors cardiovascular, pulmonary, neurologic, and renal functions, and manages hemodynamic
changes during the perioperative period to minimize side
effects while decreasing postoperative pain and recovery
times. The anesthesia provider thus faces several challenges,
one of which is choosing an anesthesia regimen that will
provide optimal intraoperative analgesia and postoperative
amnesia while allowing for a rapid, yet safe emergence and
minimal postoperative side effects [2].

S2

2. Clinical considerations in
anesthesiology practice
Choice of anesthetic approach (local, regional, general, or
combination) affects patient outcomes. Factors that affect the
choice of anesthetic regimen include anesthesia history,
medical comorbidities, anatomical, lung function, type and
length of surgery, anticipated level of physical manipulation
during the surgical procedure, and, subsequently, the level of
anticipated pain. These and other factors aid in planning the
anesthetic approach. Although certain factors such as
smoking, obesity, diabetes, and high blood pressure (BP)
may increase the risk of complications with general
anesthesia, it remains the preferred anesthetic approach for
major surgeries [5].

3. Risk of intraoperative complications:

wakefulness and hemodynamic changes
The anesthesia provider distinguishes the risks from the
anesthetic agent versus those contributed by the patient,
allowing the technique to be individualized to a patients
particular needs. While anesthesia-specific factors relate
to drug effects, patient-specific factors (eg, medical comorbidities) must be analyzed, so that the best efforts of
the anesthesia provider are implemented to avoid intraoperative complications.
One important consideration is the depth of anesthesia to
be achieved for the intervention. While moderate sedation
may be useful for short procedures, general anesthesia with
complete unawareness is a necessity for surgical interventions. Inappropriate doses of the principal anesthetic,
depression, daily alcohol use, use of certain drugs, and
iatrogenic errors increase the risk of unintended intraoperative awareness [6].
Hemodynamic changes defined as decreased or increased heart rate and/or BP are also important considerations. While hypertension and tachycardia have been
associated with inadequate anesthesia, hypotension and
bradycardia are side effects of anesthetic agents. In addition,
the type of procedure (cardiovascular or noncardiovascular), duration of procedure, and patient comorbidities
strongly influence the range of perioperative hemodynamic
changes. The challenge is to administer patient-individualized anesthesia and achieve hemodynamic balance or
prevent hypertension, hypotension, tachycardia, and bradycardia. Furthermore, hemodynamic changes also occur in
response to actions (eg, application of vascular clamps)
during surgical procedures [79].
The American Society of Anesthesiologists (ASA)
physical status classification system [10] and the American
College of Cardiology and American Heart Association 2007
Guidelines on Perioperative Cardiovascular Evaluation and
Care for Noncardiac Surgery [1113] are available to aid

J.E. Mandel
anesthesia providers in the stratification of patients based on
their overall risk of morbidity and mortality from their
surgery and the anesthetic regimen.

4. Practice recommendations for general

anesthesia
The practice recommendations by the ASA recently were
updated for the management of acute pain in the
perioperative setting. These guidelines recommend measures to be taken before, during, and after the procedure to
achieve minimal or no postoperative pain [14]. The updated
ASA guidelines recommend institutional policies and
procedures to ensure that all healthcare personnel are
familiar with safe and efficacious techniques for adequate
perioperative pain management. These include ongoing
education and training, standardized and validated instruments, and a pivotal role for anesthesiologists in
developing, maintaining, and implementing policies
[15,16]. For preoperative evaluation of the patient, the
updated guidelines recommend including a directed pain
history, a directed physical examination, and a plan for pain
control. The guidelines recommend treatment of preexistent
pain, preoperative initiation of therapy for postoperative
pain management, and adjusting or continuing medications
before the procedure to avoid an abstinence syndrome.
Education and preparation of the patient for the procedure to
encourage reporting of pain, use of adequate analgesic
methods, and reduce side effects and anxieties are also
recommended [14,1719]. More specifically, therapeutic
options such as epidural or intrathecal opioids, systemic
opioid as a patient-controlled analgesic, and regional
techniques must be considered based on a risk-to-benefit
assessment for individual patients. The updates also
recommend patient-individualized multimodal techniques
such as nonsteroidal anti-inflammatory drugs (NSAIDs),
cyclooxygenase-2 (COX-2) inhibitors, acetaminophen, and
local anesthetics in combination with perioperative techniques for pain management. The updated guidelines also
note that pediatric, geriatric, critically ill, and cognitively
impaired patients, and those patients with communication
difficulties would require additional interventions for
optimal perioperative pain management. Historically,
pediatric patients constitute an undertreated subpopulation
for perioperative pain management and therefore proactive
pain management approaches that are developmentally
appropriate are recommended. The guidelines also recommend multimodal approaches and highlight the need for
addressing the emotional component of pain management in
pediatric patients. In the case of geriatric patients,
perioperative strategies that include effective pain assessment tools, multimodal techniques, assessment of comorbidities, and dose titrations with regard to polypharmacies
and side effects are recommended. Furthermore, geriatric
patients may require extensive, proactive evaluation and

Short-acting opioids in general anesthesia

S3

questioning to recognize unrelieved pain, comorbidities,

and use of alternative and complementary agents.

may have deleterious effects in critically ill and pediatric

patients [27,28].

5. Commonly used agents for induction and

maintenance of general anesthesia

6. Total intravenous anesthesia

A plan for general anesthesia includes using a combination of agents that rapidly induce the desired operating
conditions without side effects and concomitant rapid
emergence and recovery from surgery. A combination of
volatile inhalational agents, intravenous (IV) hypnotics and
sedatives, muscle relaxants, and opioids are used to induce
and maintain general anesthesia in current practice.
Intravenous propofol, etomidate, and ketamine are
commonly used as induction as well as maintenance
agents. Propofol is principally used in the United States
due to its favorable recovery profile and short elimination
half-life. Propofol is an IV hypnotic compound that
activates gamma aminobutyric acid (GABA) receptors,
inhibits N-methyl-D-aspartate receptors, and modulates
calcium influx through slow calcium ion channels, thereby
acting as a global central nervous system depressant.
Propofol is also associated with decreased postoperative
nausea and vomiting (PONV) [20]. However, propofol may
cause a burning sensation on injection (ie, the most
common side effect) and has been known to cause
bradycardia and hypotension [8,21,22].
Compared with propofol, etomidate and ketamine have
lower rates of hemodynamic instability. Etomidate is
preferred over propofol when vasodilation and cardiac
depression are contraindicated. However, etomidate has
been associated with adrenal insufficiency, higher incidence
of PONV, and a burning sensation on administration [23].
Ketamine is preferred over propofol in patients with a
reactive airway due to its bronchodilatory properties.
Although ketamine is a rapid analgesic that preserves
respiratory drive in patients, it may stimulate the cardiovascular system and cause hallucinations, vivid dreams, or
delirium. Benzodiazepines are used in combination with
ketamine to improve its side effect profile [24], but may slow
emergence and time to discharge.
In order to maintain general anesthesia, volatile
inhalation agents including sevoflurane, desflurane, and
nitrous oxide (N2O), are commonly used. The use of
volatile agents is common practice due to ease of
administration, reliable recovery, safety, and cost. In
some cases, hepatotoxicity has been reported in isolated
cases with sevoflurane and desflurane [25,26]. Nitrous
oxide is utilized in combination with sevoflurane or
desflurane since it provides fast, reliable recovery and
lowers the risk of myocardial depression. However, nausea
and vomiting is a common side effect of intraoperative N2O
[27]. Other side effects associated with N2O include
diffusional hypoxemia, pulmonary bleb rupture, pneumothorax expansion, and inactivation of vitamin B12, which

Total intravenous anesthesia (TIVA) with propofol alone

or in combination with the opioids morphine, fentanyl,
sufentanil, alfentanil, or remifentanil has been used for
general anesthesia. Opioids act as -opioid receptor agonists
and their side effects include bradycardia, hypotension,
respiratory depression, pruritus, laryngeal rigidity, PONV,
delayed emergence, tolerance, and dependence due to
continued use [29]. While most of the afore-mentioned
side effects are associated with morphine, the short-acting
opioids, including fentanyl and its analogs (alfentanil,
sufentanil, and remifentanil), are advantageous for their
shorter onset of action times, improved potency, and minimal
histamine release [29].
In the past decade, maintenance with TIVA has gained
favor as an alternative technique to maintenance with volatile
agents in certain patients (combative pts, pediatric pts) and
due to patient preference and reduced PONV [26,2931]. As
such, it has been used more frequently for ambulatory
procedures including breast biopsies, bronchoscopies, and
tonsillectomies, as well as for some cardiovascular procedures and pediatric surgeries [3240]. It is also gaining
wider use (and may be highly frequent in some centers) for
surgeries that require the patient to be responsive during
surgery, as with some neurosurgical procedures such as
craniotomy [41,42].

7. Studies of short-acting opioids

Continuous infusions of propofol alone or a combination
of agents are widely used, with a preference for propofol
combined with alfentanil or remifentanil [37,4346]. In a
randomized trial of 49 patients undergoing elective abdominal prostatectomy, TIVA with propofol and remifentanil
was associated with decreased PONV and similar Postanesthesia Care Unit discharge times and Mini-mental Status
scores as compared with volatile gas anesthesia with
desflurane and fentanyl [47]. A combination of propofol
with short-acting opioids is also preferred over propofol
alone due to the synergy displayed by the combination and to
its lower adverse effect profile [48].

8. Advantages of short-acting opioids in the

maintenance of general anesthesia
The use of short-acting opioids provides the advantage of reducing the dose of volatile agent as well as

S4

J.E. Mandel

Table 1

Onset and offset rates of short-acting opioids [4952]

Pharmacokinetics

Alfentanil

Fentanyl

Remifentanil

Sufentanil

Onset: blood-effect site equilibration (mean)

Organ-independent elimination
Nonspecific esterase metabolism
Offset: context-sensitive half-time (mean) a

0.96 min
No
No
50-55 min

6.6 min
No
No
N 100 min

1.6 min
Yes
Yes
3-6 min

6.2 min
No
No
30 min

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 do to accumulation.

hypnotic anesthetic agents, thereby reducing the incidence of side effects and enabling faster recovery. This
control is important for patients who require tight
intraoperative control.
These short-acting opioids demonstrate distinct pharmacokinetics/pharmacodynamics (PK/PD) profiles that are
associated with rapid onset and offset, enabling faster
induction and emergence rates (Table 1) [4952]. While
fentanyl and sufentanil demonstrate an onset time of
approximately 6.6 and 6.2 minutes, respectively, onset of
alfentanil and remifentanil occurs within 0.96 and 1.6
minutes, respectively. The offset time of morphine is
approximately 180 to 240 minutes, fentanyl is 20 to 30
minutes, alfentanil is 5 to 20 minutes, and remifentanil is 3 to
6 minutes. In addition, alfentanil and remifentanil display
small volumes of distribution at a steady state, short blood
brain equilibration time, and decreased t1/2 (terminal
elimination half-life) [7,5355].
Opioids act in synergy with hypnotics to produce a
clinical effect; the sum is greater than the parts. The
interaction between propofol and remifentanil is depicted
in Fig. 1. While remifentanil has some synergistic effect on
loss of eye opening, it is far more synergistic for rendering
patients unresponsive to noxious stimuli. As the remifentanil
concentration increases, the dose of propofol required to

achieve unresponsiveness decreases below that which is

required to have the patient unresponsive to a verbal
command in the absence of remifentanil. This synergy
allows for the use of drugs such as propofol without
prolonged emergence times.
An important concept in anesthetic pharmacokinetics is
context sensitivity. Remifentanil has the shortest half-life.
Fentanyl quickly becomes context-sensitive, as a 10-hour
infusion has a half-life of almost 5 hours. Vuyk et al [48]
examined this issue in simulation, looking for the combinations of propofol and opioids that would result in the briefest
transition from surgical anesthesia to awakening, as depicted
in Fig. 2.
In this simulation, an effect site concentration of 1.6 g/
mL of propofol is required for emergence. When using
fentanyl, a 23% decrement in opioid concentration takes as
long as the decrease from 5.2 g/mL of propofol: 41 minutes.
Conversely, with remifentanil, an 80% decrement occurs in
the time required for propofol to decrease from 2.6 g/mL:
11 minutes. Thus, remifentanil allows the reduction of
propofol to significantly speed emergence.
While remifentanil is cleared by nonspecific blood and
tissue esterases, other short-acting opioids require hepatic
clearance [56]. Remifentanil may be used effectively in
patients with hepatic or renal failure. When used in

Fig. 1 Isobologram for 90% probability of lack of response to

laryngoscopy (green) and eye opening to command (blue).

Fig. 2 Opioid-propofol combinations yielding the shortest time

from surgical anesthesia to awakening. (Adapted from Vuyk et al.
Anesthesiology 1997;87:154962.).

Short-acting opioids in general anesthesia

combination with propofol or volatile agents, remifentanil
has shown a faster onset, an offset with minimal drug
accumulation, a rapid response to titration, and remarkable
synergy marked by significant reduction in the amount of
propofol or volatile agent required to achieve the desired
anesthetic effect compared with the other fentanyl-based
drugs [48]. For instance, hemodynamic instabilities due to
propofol administration may be significantly lowered with
the inclusion of short-acting opioids [7,54,55].
The dose of short-acting opioids, particularly remifentanil, in combination with induction agents is adjusted by age
and weight to achieve light as well as deep anesthesia
[57,58]. Use of short-acting opioids may be of considerable
benefit in fast-track surgeries and procedures, in patients
requiring tight intraoperative control, and neurological
assessment postsurgery.
In addition, general anesthesia has been achieved
successfully with short-acting opioids [56]. The use of
short-acting opioids enables rapid induction, optimal operative conditions, and quick recovery with few side effects.
Faster offset, easy titratability, and decreased accumulation,
especially of remifentanil, are particularly useful for
managing intraoperative responses during maintenance of
general anesthesia. In several comparative, randomized
clinical trials, use of short-acting opioids during the
induction and maintenance of general anesthesia in surgical
patients resulted in effective analgesia and attenuated
responses to various stimuli. These include attenuated stress
response to endotracheal intubation, intubation without the
use of a muscle relaxant, Laryngeal Mask Airway placement,
and fast-track coronary artery bypass grafting surgery [59].
Unexpected changes in surgical plans such as increased or
decreased duration due to complications or unexpected
findings require the administration of the anesthesia for
longer or shorter duration. Such situations are easily
addressed with the use of short-acting opioids, which do
not accumulate over time and do not burden the patients
physiology. The postoperative recovery time for remifentanil
is comparatively faster than other short-acting opioids.
Remifentanil was also associated with faster extubation
rates, decreased respiratory events requiring naloxone
treatment, and increased postoperative analgesic requirements [57,58,60,61].
Though short-acting opioids may be safely used in
various applications, potential side effects such as bradycardia, hypotension, respiratory depression, PONV, and
shivering are possible [62]. Some of these side effects are
managed pharmacologically [63,64]. Since the analgesic
effect of short-acting opioids dissipates quickly, introduction
of long-acting analgesia in a timely manner is important to
prevent residual pain from the surgery or procedure [65]. In
the absence of a postoperative analgesic care plan, use of
short-acting opioids may be disadvantageous, especially if
pain is expected after the procedure. Typically, traditional
opioids, acetaminophen, or NSAIDs are administered for
postoperative pain management before discontinuation of

S5
perioperative opioids [14]. If short-acting opioids are utilized
for postoperative analgesia or supplementation of regional
anesthesia, careful monitoring is recommended [53].

9. Summary
To achieve better surgical outcomes, improved perioperative care coupled with effective postoperative pain
management strategies are critical. Guidelines from the
ASA recommend routine implementation of procedurespecific, evidenced-based pain management protocols in
the perioperative and postoperative period that are a direct
result of preoperative assessment. The role of the
anesthesiologist is paramount to developing an effective
anesthetic plan in the current fast-track surgery environment, which requires the use of appropriate short-acting
anesthetic agents. Indeed, the choice of perioperative
anesthetic agents in consultation with the anesthesiologist,
surgeon, and the patient is crucial to the success of fasttrack interventions. To this end, the ideal anesthetic agent
should provide immediate and reversible analgesia in
combination with providing precise control and predictability for the anesthesiologist without any lingering
effects. Currently, there is no single agent that fulfills
these conditions.
The new fentanyl-based short-acting opioids administered
in combination with propofol-based TIVA or volatile
inhalational agents have demonstrated significant efficacies
in fast-track surgeries and interventional procedures [65].
Consequently, these agents have become more widely
employed by anesthesia providers to achieve various
anesthetic effects from mild sedation to deep anesthesia.
However, it is of utmost importance that the individual PK/
PD characteristics of the different short-acting opioids are
understood. The contraindications and utility of these
agents in special populations to decrease side effects
would further ensure safe and efficacious use. In particular,
the short-acting opioid remifentanil with its rapid onset and
offset, decreased accumulation, and easy titration make it
an attractive drug for improving the overall patient
experience when used in combination with hypnotic agents
[53]. Other advantages, in particular with remifentanil,
include decreased hemodynamic side effects, and neurohumoral stress response to surgery [66].

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