Considerations for the use of short-acting opioids in general anesthesia

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1 Journal of Clinical Anesthesia (2014) 26, S1 S7 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 Elsevier Inc. All rights reserved. 1. Introduction Funding 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: address: mandelj@uphs.upenn.edu. 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] /$ see front matter 2014 Elsevier Inc. All rights reserved.

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 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 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 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 J.E. Mandel 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 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

3 Short-acting opioids in general anesthesia 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]. S3 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 (N 2 O), 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 N 2 O [27]. Other side effects associated with N 2 O include diffusional hypoxemia, pulmonary bleb rupture, pneumothorax expansion, and inactivation of vitamin B 12, which 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 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 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 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

4 S4 J.E. Mandel Table 1 Onset and offset rates of short-acting opioids [49 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 Offset: context-sensitive half-time (mean) a min N 100 min 3-6 min 30 min a 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) [49 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 t 1/2 β (terminal elimination half-life) [7,53 55]. 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 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 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: ).

5 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 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 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]. 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