Anesthetic Regimens with Short-acting Opioids for Tight Intraoperative Control: A Case-based e-Newsletter
Overview of the Role of Short-acting Opioids in Anesthesia
Opioids play a central role in the management of perioperative pain, however, they are associated with a number of significant side effects, which include respiratory depression, bradycardia and hypotension, histamine release, pruritus, nausea, vomiting, and constipation.(1) In an effort to circumvent at least some of these undesirable effects, a number of synthetic options have been developed. Among these are fentanyl and its congeners, alfentanil, sufentanil, and remifentanil. Because they are shorter acting than their nonsynthetic predecessors and do not have active metabolites, these newer agents may result in fewer adverse reactions and, moreover, are associated with several advantages that make them well suited to maintaining close intraoperative control of anesthesia.(2)
Structure and Mechanism of Action
Fentanyl, alfentanil, sufentanil, and remifentanil are synthetic opioids of the 4-anilidopiperidine group, all of which demonstrate high mu opioid receptor affinity and, due to their lipophilic properties, good distribution across tissues following intravenous (IV) administration.(3) In addition, these agents are associated with an analgesic potency that exceeds that of the prototypical opioids, accompanied by both a faster onset and shorter duration of action.(3) Among its synthetic counterparts, remifentanil is unique in possessing an ester linkage. This structure, in turn, endows it with a distinct pharmacokinetic profile (to be discussed in detail below) that renders it particularly valuable for use under circumstances requiring rapid, titratable, intense analgesia of variable duration.
Like other opioids, fentanyl and its derivatives interact with the mu, kappa, and delta opioid receptors. Of these, the mu subtype appears to be the most important in terms of analgesia and respiratory-related opioid effects.(4) There are at least 2 mu receptors: mu-1, which likely mediates analgesia, and mu-2, which likely mediates respiratory depression, bradycardia, and physical dependence.(5) The brain regions responsible for mediating these effects have been well characterized and include the medulla, spinal cord, spinal trigeminal nucleus, and periaqueductal grey area.(5,6)
Relative to the classic nonsynthetic opioids, all of the newer synthetic formulations demonstrate a rapid rate of onset and time to peak effect. Nevertheless, even among agents belonging to this subcategory, pharmacologic distinctions exist that can have important implications for clinical application. Alfentanil and remifentanil, for instance, are characterized by a small volume of distribution (VD; 0.5-1 L/kg and 300-400 mL/kg, respectively) and increased diffusibility resulting from a pKa that is below physiologic pH (6.5 and 7.0, respectively).(7-9) Together, these properties combine to decrease their time to peak effect (60-90 seconds) relative to the other short-acting opioids, fentanyl (VD=4.0-6.0 L/kg; pKa=8.0; onset=3-5 minutes) and sufentanil (VD=2.0-3.0 L/kg; pKa=8.5; peak effect=3-5 minutes).(7-11)
Similarly, there are also significant differences in rate of elimination among the short-acting opioids. In contrast to fentanyl, sufentanil, and alfentanil, all of which undergo metabolism in the liver (the predominant organ of metabolism for opioids), remifentanil is a substrate for nonspecific esterases and is therefore metabolized in the blood and other tissues.(12) As a result, it has an extremely rapid rate of clearance (on the order of 40-60 mL/min/kg in young, healthy adults), which combined with its low volume of distribution, translates into limited drug accumulation and a requirement for continuous infusion in order to maintain its effect.(8) The fact that it is not subject to any appreciable accumulation is an important distinguishing characteristic worth highlighting. While all of the short-acting opioids are associated with fewer adverse reactions compared with traditional opioids, a risk for accumulation with continuous infusion remains a concern, except in the case of remifentanil. This risk becomes an especially important consideration in the management of critically ill patients, who often exhibit significantly reduced drug clearance because of a number of factors including illness, organ dysfunction, or concomitant therapy.(2)
The rapid titratability demonstrated by remifentanil, and to some extent the other short-acting opioids, represents a powerful tool in the context of procedures where prompt adjustments in the level of analgesia are required.(13) The utility of this becomes apparent when considering the analgesic requirements of various perioperative stimuli. Previous work has demonstrated significant variability in the concentration of opioid required to inhibit patient response to intubation, skin incision, or skin closure.(14) As a result, it has been recommended that the rate of opioid infusion be adjusted according to patient responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions, as well as provide rapid recovery of consciousness and spontaneous ventilation.(14)
To evaluate the implications of pharmacologic differences among the various short-acting opioids, combined evidence from computer modeling and clinical studies has been used to characterize their relative pharmacokinetic profiles.(1,13) Data from simulated bolus opioid administration has shown a wide range across agents in predicted latency to reach peak effect site concentration and subsequent dissipation.(1) Noteworthy is the distinct pharmacokinetic profile of remifentanil relative to its peers. The predicted pattern of effect following a bolus injection of remifentanil equates to a rapid pulse administration, with achievement of peak concentration followed by a return to an effect site concentration of <40% within 5 minutes of delivery.(1) In the context of continuous opioid infusion, predicted onset times across all agents are similarly short, with a mean time required to achieve steady-state effect site concentrations (ie, infusion front-end kinetics) occurring within 5 minutes for each.(1) However, the predicted offset time after termination of a steady-state infusion (expressed by the context-sensitive half-time) ranges substantially depending upon the particular opioid.
Short-acting Opioids in Practice
Armed with a comprehensive knowledge of available anesthetic options that includes an understanding of short-acting opioid pharmacokinetics, practitioners are confronted with the challenge of choosing the most appropriate regimen/technique for a given patient. To accomplish this goal, the primary concerns associated with each approach must be identified and weighted accordingly. Previously identified factors that require consideration include, but are not limited to, the following:
- Type of surgery (duration, analgesic requirements, monitoring requirements)
- Patient medical history/comorbidities
- Presence of reduced drug clearance capacity due to illness or concomitant medication
- Need for intraoperative monitoring
- Patient risk for postoperative nausea and vomiting (PONV; exacerbated by regimens having an inhalation component)
- Economic costs
A good demonstration of the differential impact that a given anesthetic can have on these factors is provided by examination of remifentanil use in general anesthesia. Previously, in a systematic meta-analysis of 85 clinical trials, remifentanil was found to be associated with a decreased rate of intraoperative tachycardia and hypertension, but an increased use of vasopressors. Postoperatively remifentanil was associated with faster recovery, less respiratory depression, and decreased use of naloxone.(15) However, it was also associated with higher postoperative analgesic requirements and increased shivering.(15) Collectively, these observations imply that remifentanil is best suited for short outpatient procedures that are unlikely to require extensive postoperative pain relief.
Because the relative contribution of these factors to the decision-making process varies significantly across cases, the approach to anesthesia is one that must be highly tailored not only to the procedure, but also to the individual history and needs of the patient. Patients with a history of respiratory disease, for example, require management that takes into account an increased probability of both perioperative and postoperative complications. Specifically, the presence of asthma is thought to significantly increase the risk for perioperative bronchospasm precipitated by instrumentation, drugs, or other complications such as aspiration, infection, or trauma.(16) Likewise, asthma has also been associated with postoperative pulmonary difficulties resulting from fluid shifts or delayed mobilization.(16) To provide a more detailed illustration of how such issues can impact the management of a patient with these types of characteristics, some of the challenges involved (as well as a potential approach to address them) will be discussed in the following case study by Dr. Adam Levine.
Case Study 1
17-year-old female with a history of nasal passage obstruction and difficulty breathing scheduled to undergo septoplasty and sinus endoscopy
While the range of considerations is necessarily broad for all cases in which anesthesia is required, there are some that are inherently more challenging due to the presence of multiple issues that must be addressed in parallel. In the case study that follows, Dr. Levine describes a patient for whom the choice of anesthetic regimen must take into account a medical history that includes multiple significant metabolic and vascular comorbidities, as well as a need for neurological monitoring.
Case Study 2
73-year-old male with coronary artery disease, type 1 diabetes mellitus, hypertension, and peripheral vascular disease scheduled to undergo right carotid endarterectomy
Intraoperative Neurophysiological Monitoring
Continuous monitoring of neurophysiologic signals during surgery enables the detection of adverse changes, so that corrective measures may be promptly applied in response. In this regard, adequate intraoperative monitoring plays a crucial role in reducing the risk of potential postoperative neurological deficits, such as weakness, loss of sensation, hearing loss, and impairment of other bodily functions. Previous studies have validated the utility of intraoperative monitoring modalities in procedures such as cervical spine surgery and thoracic and lumbar laminectomy. Currently, the main modalities for monitoring include the following(17):
- Somatosensory evoked potentials
- Motor evoked potentials
It should be pointed out that while both inhaled and IV agents blunt signal attainment, inhaled agents are associated with greater depression and are thus relatively contraindicated in cases requiring monitoring. In the final case study below, Dr. Levine will review additional considerations for such a case in which the capacity to closely monitor the patient’s neurophysiological status is crucial to optimize the postoperative outcome.
Case Study 3
42-year-old female scheduled to undergo a multilevel laminectomy with lumbar fusion
As noted in the previous sections, as well as the case vignettes, the use of short-acting opioids has played an important role not only in intraoperative management, but also in the prevention of negative outcomes during the postoperative period. Indeed, substantial attention has been focused on their application towards meeting postoperative needs for pain control and the minimization of risk for PONV.
Previously, it has been reported that over 80% of surgical patients experience moderate pain and 31% to 37% experience severe or extreme pain following surgery.(18) Pain that persists beyond the typical healing period is a significant issue for surgical patients because of the potentially negative impact on health outcomes in both the short and long terms. Specifically, good pain control has been shown to be important for the prevention of negative events, including tachycardia, hypertension, myocardial ischemia, decreased alveolar ventilation, and poor wound healing.(19) In addition, postoperative pain has been identified as a significant cause of delayed discharge after ambulatory surgery.(19)
Traditionally, opioids have widely been considered to be the cornerstone of effective postsurgical pain management because of their ability to effectively target central mechanisms of pain perception.(20) In particular, administration of short-acting opioids has emerged as a preferred strategy to address the frequent requirement for rapid onset of analgesia and the ability to titrate analgesia to the changing characteristics of pain over a short period. In their most recent guidelines, the American Society of Anesthesiologists (ASA) describes evidence in support of perioperative administration of opioids via a number of potential techniques for postoperative pain management.(21)
A major concept in the management of postoperative pain is that it should be highly individualized, taking into account frequency of pain over the course of a 24-hour day and thereafter, frequency and duration of pain flares, and presence of neuropathic pain.(21,22) Consideration of these factors is crucial to help guide the choice of pharmacologic treatment to meet the needs of the patient. Use of a multimodal approach employing several agents to decrease pain receptor activity and diminish the local hormonal response to injury is preferred to comprehensively address the pathophysiology of postoperative pain.(21) Specific recommended strategies that utilize different agents include the following:
- Continuation of short-acting opioids
- IV administration of nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen
- Infiltration of the wound with a long-acting local anesthetic
- Epidural activation (opioid and/or local anesthetic)
- Administration of long-acting opioids 20 to 30 minutes before discontinuation of some short-acting opioids
- Major nerve block
In addition, other strategies that involve altering temporal aspects of anesthetic dosing may be effective; stepwise tapering of remifentanil at the end of surgery results in a decrease in postoperative pain scores, and reduced rescue analgesic requirement was observed following remifentanil-desflurane anesthesia in patients with thyroidectomy.(23)
Under certain circumstances, opioids can also activate pain facilitatory pathways, enhancing sensitivity to noxious stimuli.(24) In observational studies, a requirement for increasing doses, as well as the development of abnormal pain, has frequently been found in association with high dosing and prolonged use of opioids.(24) In an effort to better characterize the clinical consequences of intraoperative doses of opioids in terms of their potential to induce hyperalgesia, a large-scale meta-analysis was recently undertaken.(25) Data collected from 27 studies (N=1491) revealed that patients treated with high intraoperative doses of opioid had a clinically small, but statistically significant, increase in pain perception compared to reference groups at 1 hour, 4 hours, and 24 hours, in addition to higher postoperative morphine use after 24 hours. Although the results were primarily associated with the administration of high doses of remifentanil, it should be noted that comparisons of other opioids were precluded by the limited availability of data on the impact of other opioids. With regard to strategies that may decrease or prevent opioid-induced hyperalgesia, some evidence suggests that concomitant administration of drugs like N-methyl-D-aspartate antagonists, alpha-2 agonists, or NSAIDs, opioid rotation, or combinations of opioids with different receptor selectivity may be effective.(24)
Postoperative Nausea and Vomiting
PONV is caused primarily by the use of inhalational anesthesia including nitrous oxide and opioid analgesics.(26) Although its reported incidence varies widely (most due to the diversity of patient populations, surgical procedures, and anesthetic regimens employed), it is generally estimated to be nearly 30%.(27,28) A number of factors that strongly influence the likelihood of experiencing PONV have been identified. These include younger age, female sex, lack of smoking, and a history of PONV or motion sickness.(29) For subgroups of patients exhibiting several of these risk factors, the incidence of PONV has been suggested to be as high as 80% in the absence of prophylaxis.(30) Although PONV has not been found to negatively impact surgical outcomes, it is clearly in the interest of both patients and healthcare providers to minimize its occurrence. In fact, patients often cite PONV as being one of the distressing aspects of postsurgery and report that they would be willing to incur greater personal cost to avoid these outcomes.(31-33) From the perspective of the clinicians and the healthcare system, development of protocols that enable more efficient control of PONV is important towards the reduction of costs that can be achieved by decreasing the time to discharge from the postanesthesia care unit.(34)
Currently, there exists a paucity of well-designed trials investigating the extent to which anesthetic choice can reduce the risk for PONV.(26) That aside, clinical evidence to date collectively indicates that the primary causes of PONV are the use of opioid analgesics (although not consistently) and/or inhalational anesthetics.(35-41) While individual agents within each of these classes might theoretically be expected to differ in relative contribution to PONV due to distinctions in their chemical properties, support for the effectiveness of substituting one agent for another is thus far lacking. For example, the use of remifentanil in lieu of fentanyl has been not been shown to significantly impact PONV incidence, despite the significantly higher rate of clearance.(42) Similarly, no benefit has been associated with the use of one commonly used inhalation anesthetic over another; both sevoflurane and isoflurane appear to have equal potency to produce PONV, and a longer duration of exposure to either is associated with greater PONV.(36)
In contrast, replacement of inhalational components of anesthesia regimens with IV agents has shown promise as an effective strategy for reducing PONV risk in a wide range of studies. Comparison of IV induction with propofol vs inhalational induction with sevoflurane (both followed by inhalational maintenance with nitrous oxide) for ambulatory surgical procedures has indicated that patients are significantly less likely to experience PONV with IV induction.(43)
Additional studies have reported that the use of total intravenous anesthesia (TIVA) is similarly associated with a reduced risk of PONV. In patients undergoing ambulatory surgery, a decreased incidence of early PONV was observed with TIVA compared with inhalation anesthesia using either sevoflurane or desflurane.(44) Likewise, in women undergoing gynecological surgery, TIVA with propofol and alfentanil compared with inhalational maintenance with nitrous oxide and enflurane was associated with less nausea and vomiting, a reduced requirement for antiemetic medication, and a lower probability of unplanned admission to hospital.(45) Collectively, these results are in agreement with a recent large-scale retrospective study of 1,405 surgical cases comparing TIVA via target-controlled infusion with propofol/fentanyl-based or desflurane/fentanyl-based anesthesia in ophthalmic procedures. The results of this analysis revealed that TIVA resulted in less PONV and a decreased requirement for rescue therapy when compared with inhalation anesthesia (11.3% vs 32.2%, P<.001 and 23.9% vs 54.0%, P=.002, respectively).(46)
Short-acting opioids have been shown to be effective and generally well tolerated in a wide spectrum of patients undergoing different types of inpatient and outpatient surgical procedures. When compared with traditional nonsynthetic opioids, these newer agents demonstrate superior analgesic efficacy, accompanied by a reduced risk of adverse effects. Additionally, their pharmacokinetic properties confer a number of characteristics that make them especially valuable options for perioperative pain management and potential improvement of postoperative recovery. These include decreased drug accumulation, rapid onset and offset, and high titratability (none of which appear to be affected by patient age, gender, or weight). Understanding the nature of these agents and being able to anticipate how they will behave in clinical application enables practitioners to formulate an anesthetic plan that can ensure smooth emergence and recovery, appropriate postoperative analgesia, and optimal overall patient experience and satisfaction.
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