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: November 4, 2013; Accepted: November 25, 2013; Published Online: January 31,
2014
DOI: http://dx.doi.org/10.1016/j.jclinane.2013.11.003
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Article Outline
1. 1. Introduction
2. 2. Clinical considerations in anesthesiology practice
3. 3. Risk of intraoperative complications: wakefulness and hemodynamic changes
4. 4. Practice recommendations for general anesthesia
5. 5. Commonly used agents for induction and maintenance of general anesthesia
6. 6. Total intravenous anesthesia
7. 7. Studies of short-acting opioids
8. 8. Advantages of short-acting opioids in the maintenance of general anesthesia
9. 9. Summary

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.

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

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
experience 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].

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 patient’s 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 [[7], [8], [9]].

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 [[11], [12], [13]]
are available to aid 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], [17], [18], [19]].
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 questioning to recognize unrelieved pain, comorbidities, and use of alternative
and complementary agents.
5. Commonly used agents for induction and maintenance
of general 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 may have deleterious effects in critically ill
and pediatric patients [[27], [28]].

6. Total intravenous anesthesia

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 μ-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], [29], [30], [31]]. 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 [[32],
[33], [34], [35], [36], [37], [38], [39], [40]]. 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], [43], [44], [45], [46]].
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 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) [[49], [50], [51], [52]]. 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 β (terminal elimination half-life) [[7], [53], [54], [55]].

Table 1Onset and offset rates of short-acting opioids [[49], [50], [51], [52]]
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
a
Offset: context-sensitive half-time (mean) 50-55 min > 100 min 3-6 min 30 min
aThe 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.

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.

Fig. 1

Isobologram for 90% probability of lack of response to laryngoscopy (green) and eye opening
to command (blue).

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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.

Fig. 2

Opioid-propofol combinations yielding the shortest time from surgical anesthesia to

awakening. (Adapted from Vuyk et al. Anesthesiology 1997;87:1549–62.).

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In this simulation, an effect site concentration of 1.6 μg/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 μg/mL of propofol: 41 minutes. Conversely, with remifentanil, an 80%
decrement occurs in the time required for propofol to decrease from 2.6 μg/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 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 patient’s 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 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 procedure-specific, 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 fast-track
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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