Opioid-free and opioid-sparing anesthesia

In light of the current opioid crisis, there has been a movement to reduce opioid use in the perioperative period. Opioid-free anesthesia (OFA) is a practice that completely excludes the use of intraoperative systemic, neuraxial, or intracavitary opioids. A related but less restrictive technique is opioid-sparing anesthesia, where small amounts of opioids are used intraoperatively. Both opioid-free and opioid-sparing techniques have shown particular value in certain patient populations. Patients with obstructive sleep apnea and those undergoing bariatric surgery are at high risk for opioid-related respiratory complications in the postoperative period. Patients suffering from chronic postsurgical pain, complex regional pain syndrome, cancer-related pain, and other opioid-tolerant patients may also benefit from opioid-free and opioid-sparing anesthetic approaches.1 History of opioid use in anesthesia One of the earliest documented uses of opioids in clinical practice was in 1853 with the subcutaneous administration of morphine by Dr Alexander Wood. However, the use of intravenous (IV) opioids as part of anesthetic practice would not be fully realized for many decades. Dr John Lundy, an early pioneer of IV opioids, first presented the idea of the "balanced anesthetic" in his publications in 1926 and 1931. Dr Lundy's method required "moderate amounts of several agents … rather than a large dose of one or large doses of two," paving the way for a new technique to supplant the dominance of ether as the primary and sole anesthetic agent.2 Rise of synthetic opioids The late 19th and early 20th centuries would see the discovery and creation of many semisynthetic opioids, derived from naturally occurring opioid compounds such as morphine. One of these was diacetylmorphine, synthesized in 1897 and brought to market under the name heroin in 1898 by Bayer. Heroin had a relatively short lifespan in clinical medicine, eventually facing an outright ban by the federal government in 1924 over concerns about its highly addictive properties and use as a street drug. Fentanyl was synthesized in 1960 and its first described use in anesthesia would come in 1962. With its effectiveness and the hemodynamic stability that it provided as part of an anesthetic, fentanyl quickly cemented the place of opioids as a routine part of the modern "balanced anesthetic."3 The opioid epidemic The current opioid epidemic in the United States can be traced back to the late 1990s, when state medical boards started to loosen restrictions on prescribing opioids for the management of chronic noncancer pain. Not long after, pain would be popularized as "the fifth vital sign," leading to widespread acceptance of aggressive pain treatment and liberalized prescribing of controlled substances. From 1997 to 2007, retail sales of opioid medications saw an overall increase of 149%, with some medications such as oxycodone seeing an increase of 866%. The modern opioid epidemic was born as a consequence. In 2012, the number of deaths related to prescription opioid use surpassed the number of deaths from suicide and motor vehicle accidents.4 Opioid-free and opioid-sparing techniques Multimodal analgesic agents The current cornerstone of minimizing opioid use in the perioperative setting is a multimodal analgesic regimen consisting of nonopioid pharmacologic and regional anesthetic techniques (Table 1). Using these methods, the anesthesiologist can take advantage of the multiple mechanisms of different pharmacologic agents that can act synergistically to achieve the goals of hypnosis, immobility, sympatholysis, autonomic stability, and intraoperative and postoperative analgesia.5Table 1: Common pharmacologic agents for multimodal opioid-sparing analgesia.Pharmacologic agents Nonsteroidal anti-inflammatory drugs (NSAIDs) NSAIDs have long been a staple in the treatment of pain due to their reliable analgesic, anti-inflammatory, and antipyretic properties. Common NSAIDs currently used in anesthetic practice include ketorolac and diclofenac, which may be administered parentally or intramuscularly. NSAIDs act by inhibiting the enzyme cyclooxygenase, which ultimately results in the blockade of prostaglandin synthesis. This in turn reduces the production of inflammatory response mediators, reducing peripheral nociception. There have also been suggestions that the analgesic effects of NSAIDs may be due to their modulation of the body's central response to noxious stimuli as a result of the blockade of prostaglandin synthesis in the spinal cord.6 In the setting of ambulatory laparoscopic procedures, Ding and White7 found that patients treated intraoperatively with ketorolac versus fentanyl reported lower pain scores, a lower incidence of nausea, and required less analgesic medications in the post-anesthesia care unit (PACU). Similarly, Wong et al8 found that in a postoperative ambulatory setting, ketorolac had a slower onset, but equal effectiveness compared with fentanyl in treating pain. Common concerns in terms of NSAID use in the perioperative period include gastrointestinal tract bleeding, platelet dysfunction, and renal injury. NSAIDs have been shown to cause a transient decrease in renal function postoperatively, but, in adults with normal preoperative renal function, this is a low risk.9 Meta-analyses examining postoperative bleeding in patients treated with ketorolac or other common NSAIDs versus controls did not show a significant difference in rates of postoperative bleeding across various surgical procedures.10 Acetaminophen/paracetamol Acetaminophen has been a widely used analgesic and antipyretic medication for both adults and children since the 1970s. It carries a favorable side-effect profile as it avoids the potential for gastrointestinal damage and negative renal effects produced by NSAIDs and does not negatively affect gastrointestinal motility or respiratory drive like opioids. Although acetaminophen has been in clinical use for decades, its mechanism of action is still not fully understood. It has been proposed that it has a mechanism of action similar to NSAIDs in that it acts through the inhibition of cyclooxygenases, but more recent evidence suggests that it may also act through the potentiation of cannabinoid/vanilloid receptors in the central nervous system.11 IV acetaminophen has shown promising opioid-sparing effects and reduced postoperative pain scores as part of multimodal pain regimens. Aryaie and colleagues demonstrated that the addition of IV acetaminophen to a postoperative colorectal recovery protocol reduced postoperative opioid consumption by 40% at 24-hour and 48-hour time points. Patients treated with acetaminophen also reported lower pain scores, had significantly reduced times to return of bowel function, and were discharged sooner than control groups.12 The timing of administration of acetaminophen is an important consideration. A meta-analysis of IV acetaminophen use at different time points during the perioperative period showed timing-sensitive effects on outcomes such as postoperative nausea and vomiting (PONV). Specifically, IV acetaminophen administered either before surgery or intraoperatively showed a significant reduction in the incidence of PONV, which correlated with reported lower pain scores, even in the absence of a significant postoperative opioid-sparing effect. This suggests that the mechanism for reduction in PONV with IV acetaminophen is associated with a reduction in pain intensity before arrival in PACU as opposed to the commonly held notion that PONV is directly related to levels of opioid administration.13 The optimal route of administration remains a question due to large price variations between the different forms of the drug. A study examining the peak plasma and cerebrospinal fluid (CSF) concentrations achieved by IV, oral (PO), and rectal (PR) dosing of 1000 mg of acetaminophen found that IV administration produced a 76% greater plasma concentration of drug compared with PO administration and a 256% greater plasma concentration of drug compared with PR administration. Because the entry of acetaminophen into the central nervous system occurs through passive diffusion, it follows that IV administration produced 60% greater CSF concentration compared with PO administration and 87% greater CSF concentration compared with PR administration.14 Despite the greater bioavailability of IV acetaminophen, there is a lack of clinical evidence suggesting the superiority of IV administration versus PO administration with respect to pain control and opioid-sparing effects. As such, other considerations such as cost or patient factors may be taken into account when selecting dosage forms until further studies are carried out.15 N-Methyl-D-aspartate (NMDA) antagonists Ketamine Clinical use of ketamine was first described in the medical literature as early as 1965. Early reports described its potential as a single agent anesthetic that could produce amnesia, loss of consciousness, immobility, and analgesia. However, soon after its introduction into clinical practice, concern for its side effects, namely disturbing emergence reactions, led to its falling out of favor. Ketamine typically exists as a racemic mixture of R(−) and S(+) enantiomers. The primary receptor target that is largely responsible for ketamine's clinical properties is the NMDA receptor. Antagonism of this receptor through noncompetitive inhibition of glutamate binding is responsible for most of the analgesic, amnestic, and psychotomimetic effects of the drug. However, ketamine has also been found to interact with non-NMDA glutamate, nicotinic and muscarinic cholinergic, monoaminergic, and opioid receptors. Further, ketamine has shown interaction with voltage-dependent sodium and L-type calcium channels, which may be responsible for mild local anesthetic effects and cerebral vasodilation, respectively.16 In a Cochrane review analyzing the effectiveness of perioperative ketamine for treating acute postoperative pain, studies were examined in which patients received either ketamine versus placebo or ketamine versus opioids or NSAIDs. The primary outcomes were opioid consumption and patient-reported pain intensity at rest and during movement at 24 and 48 hours postoperatively. Results were consistent across the wide variety of surgeries and indicated that ketamine reliably reduced postoperative analgesic requirements and pain intensity. In patients who had received perioperative ketamine, postoperative opioid consumption was reduced by 19% at 24-hour and 48-hour time points. Pain scores were decreased by 19% at rest and 14% during movement at the 24-hour postoperative time point. The majority of studies used bolus ketamine dosed from 0.25 to 1 mg/kg or an infusion rate of 2 to 5 mcg/kg/min.17 However, other studies have found that ketamine does not enhance postoperative recovery. A randomized, double-blind, placebo-controlled trial of patients undergoing laparoscopic cholecystectomy evaluated the effect of low-dose ketamine on quality of recovery using the Quality of Recovery Questionnaire (QoR-40) and objective PACU recovery parameters. Study groups were randomized to receive a single bolus injection of saline, ketamine 0.2 mg/kg, or ketamine 0.4 mg/kg before surgical incision. The results of the study showed no significant difference in QoR-40 scores at 24 hours after surgery and no significant difference in time to eye opening, length of PACU stay, pain scores, or opioid analgesic requirements in the PACU.18 Magnesium Magnesium exists as the second most common intracellular cation and the fourth most common plasma cation. It has a wide range of effects on the regulation of transmembrane ion exchange and enzymatic reactions. In the clinical setting, magnesium is typically used as an antiarrhythmic and tocolytic agent. Although not commonly considered as an analgesic agent, magnesium has also been shown to act as an NMDA receptor antagonist. This property, in addition to its role as a calcium channel blocker, leads to its potential as an analgesic adjunct.19 A meta-analysis evaluating the effectiveness of IV magnesium as an analgesic adjunct revealed significant effects, reducing postoperative opioid consumption and early (0 to 4 h) and late (24 h) pain scores. Early pain with movement (0 to 4 h) was not reduced with magnesium, but late pain with movement (24 h) was improved. Intraoperative magnesium administration across the studies included in the meta-analysis used magnesium bolus doses ranging from 30 to 50 mg/kg, followed by variable infusions at rates ranging from 8 to 25 mg/kg/h. Magnesium toxicity remains a concern with prolonged magnesium infusions, but no reports of clinical magnesium toxicity were found among the study participants.20 In addition to its opioid-sparing properties, magnesium has been shown to improve hemodynamic stability intraoperatively. Forget and Cata examined the role of IV magnesium in mitigating hemodynamic responses to major noncardiac surgery. A meta-analysis showed that magnesium significantly reduced heart rate variability compared with placebo, but there was no effect on blood pressure. Although heart rate stability is associated with adequate analgesia under anesthesia, it is difficult to differentiate whether heart rate stability was truly due to the antinociceptive effects of magnesium or if it was instead a direct effect of the antiarrhythmic effect of magnesium.21 Gabapentinoids Gabapentin and pregabalin are structural analogs of gamma-aminobutyric acid (GABA) that, despite having analogous structures to GABA, function through binding to alpha-2-delta subunits of voltage-dependent sodium channels in active neurons. Binding at these receptors has been found to inhibit the development of hyperalgesia and central sensitization. Gabapentin has been established for use in the treatment of chronic neuropathic pain particularly from diabetic neuropathy, postherpetic neuralgia, and complex regional pain syndrome.22 Although pregabalin and gabapentin are often used interchangeably for an intended analgesic and opioid-sparing effect, their clinical effectiveness varies. A meta-analysis of postoperative pain in patients receiving pregabalin versus placebo showed that perioperative administration of pregabalin did not significantly reduce pain intensity in the first 24 hours after surgery. The analysis did, however, show that pregabalin significantly reduced opioid consumption during the same period. Patients receiving pregabalin also had a lower incidence of vomiting, but an increased incidence of blurred vision.23 Whereas pregabalin failed to reduce pain intensity, gabapentin has shown more promising clinical outcomes. A systematic review by Ho et al22 examining the role of gabapentin in acute postoperative pain management revealed that preoperative administration of gabapentin was effective in reducing both pain scores and opioid requirements. Similarly, a meta-analysis by Hurley and colleagues showed a significant decrease in visual analog scale pain scores during the first 4 hours postoperatively and at 24 hours in patients treated with preoperative gabapentin. A decrease in postoperative opioid usage was also found in patients receiving gabapentin versus placebo. Dosages of gabapentin across studies most consistently ranged from 300 to 1200 mg and were generally administered as a single dose 1 to 2 hours before surgery.24 With respect to common side effects, there did not appear to be a consistent decrease in measures of nausea, vomiting, or dizziness across studies. There did, however, appear to be a significantly higher incidence of postoperative sedation in patients receiving gabapentin.22,24 Parenteral local anesthetics IV use of local anesthetics such as procaine and lidocaine for analgesia has been reported in the literature since the 1940s. Proposed mechanisms for local anesthetic-induced pain relief have included selective depression of pain transmission at the level of the spinal cord and a reduction in the discharge of tonically active peripheral nerves. The clinically effective serum concentration of lidocaine for analgesia has been estimated at 2 to 10 mcg/mL in animal models, which adequately reduces tonic injury discharge from A-delta and c fibers without affecting baseline axonal nerve conduction.25 In addition, it has been suggested that lidocaine used at plasma concentrations insufficient to block sodium channels is still able to suppress the release of inflammatory cytokines and act as an NMDA receptor antagonist.26 The efficacy of systemic lidocaine for postoperative pain management in abdominal surgery was examined by a meta-analysis comparing lidocaine with a placebo. Significantly decreased postoperative visual analog scale pain scores were seen at 6-hour and 24-hour time points, whereas pain scores at 72 hours postoperatively were not significantly different. Patients treated with lidocaine also showed significantly decreased postoperative opioid consumption during the first 48 hours postoperatively and decreased time to first flatus and bowel movement.27 Similarly, a randomized-controlled trial examining the effect of IV lidocaine on recovery in laparoscopic cholecystectomy showed significantly reduced pain intensity for up to 6 hours postoperatively, reduced opioid consumption up to 24 hours postoperatively, and decreased time to first flatus and bowel movement. In addition, serum concentrations of IL-6 and IL-8 were measured at the end of the procedure and 12 hours postoperatively and lidocaine-treated patients showed less cytokine release, confirming lidocaine's multiple beneficial mechanisms of action in mitigating surgical stress.28 Dexmedetomidine The usefulness of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine) as an anesthetic agent was first described in the literature in 1988. Segal et al29 described the ability of the d-enantiomer of medetomidine (dexmedetomidine) to lower the MAC for halothane in rats through presynaptic alpha-2 agonism, which results in sympatholysis, and postulated a postsynaptic centrally mediated mechanism of modulation of neuronal excitability. Dexmedetomidine was approved for clinical use by the FDA in 1999. Its centrally mediated sedative mechanism has been elucidated as an alpha-2-adrenoceptor-mediated inhibition of the pontine locus ceruleus that leads to disinhibition of ventrolateral preoptic nucleus firing, resulting in increased GABA release. This subsequently leads to inhibition of the tuberomammilary nucleus, which is responsible for wakefulness, explaining the ability of dexmedetomidine sedation to mimic endogenous non-rapid eye movement sleep.30 IV dexmedetomidine has been shown to produce significantly decreased postoperative pain scores, increased opioid-free time intervals in the PACU, and opioid-sparing effects for up to 24 hours postoperatively compared with placebo and fentanyl.31,32 However, prolonged PACU stays have also been seen with dexmedetomidine in randomized controlled trials. Further, dexmedetomidine-treated patients have shown an increased time to emergence from anesthesia, which raises the question of whether postoperative sedation could partially explain the increased opioid-free intervals. Pestieau et al31 explored this issue using a Cox proportional hazard model and showed that the increased opioid-free interval and lower opioid rescue requirement were robust findings despite the longer emergence times and PACU stays. Nevertheless, attention should still be paid to the potential sedative effects of dexmedetomidine, and dosage adjustments should be considered with dexmedetomidine administration in elderly patients. With respect to other side effects, bradycardia, hypertension, and hypotension are common concerns with dexmedetomidine use. Hypertension typically occurs at higher plasma concentrations such as those achieved with bolus administration and gives way to hypotension with decreases in plasma concentration.33 Symptomatic bradycardia requiring treatment has been consistent across many trials and appears to be affected by the method of administration, with bolus administration showing higher risks for bradycardia compared with continuous infusion. Despite the increased incidence of bradycardia, significant increases in the relative risk of hypotension requiring active treatment have not been observed.32 Dexamethasone Dexamethasone is a low-cost synthetic adrenocortical steroid with high glucocorticoid activity that has traditionally been used to reduce PONV and postoperative inflammation. However, it has also shown potential in improving postoperative pain and reducing discharge times from day surgery units. A meta-analysis examining the effects of perioperative dexamethasone on postoperative analgesia showed significantly lowered pain scores, an opioid-sparing effect at 2 and 24 hours, and reduced PACU stays. Study doses of dexamethasone ranged from 4 to 20 mg, with the most common dosage being 8 mg. There was no evidence of a dose-dependent effect on opioid requirements and a small but significant dose-dependent effect on 24-hour pain scores.34 Comparable results were found in patients receiving dexamethasone during laparoscopic cholecystectomy. Patients reported lower postoperative analgesic requirements and a reduced length of hospitalization compared with controls. In the same study, dexamethasone was also shown to significantly improve emotional state, pain scores, nausea, and fatigue as reported by the QoR-40 scoring system.35 Despite its many benefits, dexamethasone also carries potentially significant side effects. Chief concerns with routine use of dexamethasone include perioperative hyperglycemia, postoperative infection, impaired wound healing, and adverse neuropsychiatric effects ranging from anxiety to psychosis. Hyperglycemia does appear to be a common complication during postoperative day 1, and caution should be exercised with administration to diabetic patients. However, there does not appear to be compelling evidence indicating an increased incidence of postoperative infection or delayed wound healing with opioid-sparing doses of intraoperative dexamethasone.34 Regional anesthetic techniques Regional anesthesia has demonstrated improved short-term recovery profiles both when compared with and used in conjunction with general anesthesia.36 In ambulatory procedures, regional anesthetics have shown lower postoperative pain scores, shorter PACU discharge times, and a lower incidence of PONV than patients receiving general anesthesia. The importance of regional anesthetics in opioid-free and opioid-sparing modalities was highlighted in a prospective study that examined 1791 patients who received 2382 mixed upper and lower extremity peripheral nerve blocks for ambulatory surgical procedures. The study demonstrated that about 90% of patients arrived to the PACU with well-controlled pain and did not require any opioid analgesics in the PACU.37 A further consideration in opioid-free and opioid-sparing modalities is pain control after patients leave the hospital setting. Chronic pain lasting months after surgery can become a significant burden. A meta-analysis examined the effect of regional anesthetic techniques on the incidence of persistent postoperative pain, defined as pain persisting beyond 3 months after surgery. It was hypothesized that by preventing central sensitization, regional anesthetic techniques could possibly improve long-term pain outcomes. The authors found that regional anesthesia used in thoracotomy, breast surgery, and cesarean section showed significant reductions in patient risk of developing persistent postoperative pain compared with standard analgesia.38 These results show the potential for regional anesthetic techniques to play an essential role in the management of perioperative pain. Emphasis is often placed on managing and reducing acute pain in the immediate postoperative period, but postoperative chronic pain syndromes are also major contributors to long-term opioid overuse. Regional anesthesia may exist as a route to reduce the burden of long-term postoperative pain. Opioid-free protocols Bariatric surgery Some of the most well-described opioid-free protocols have been used in the realm of bariatric surgery. Patients undergoing bariatric surgery often suffer from obstructive sleep apnea and are at a high risk for adverse events from opioid-related side effects. Mauermann and colleagues reported an opioid-free protocol that revolves around a multimodal analgesic regimen (Fig. 1).39 Ketamine (0.25 mg/kg IBW), magnesium (40 mg/kg IBW), lidocaine (1.5 mg/kg IBW), and dexmedetomidine (1 mcg/kg IBW) were administered as bolus doses at the induction of anesthesia, with the exception of dexmedetomidine, which was administered at least 10 minutes before induction. The analgesic medications were then continued during the procedure as continuous infusions until the end of the procedure, with the exception of ketamine, which was discontinued 30 minutes before the end of the procedure to minimize potential psychotomimetic side effects. Induction and intubation were achieved with propofol and rocuronium and maintenance was achieved with desflurane titrated to a Bispectral Index Scale (BIS) of 40 to 60. Dexamethasone, droperidol, and ondansetron were administered for PONV prophylaxis and acetaminophen and NSAIDs were also administered at the end of the procedure. With a well-structured protocol in the setting of a consistent, minimally invasive surgery, the authors were able to create a reliable anesthetic with minimal or no opioids.39Figure 1: Timing and dosing of multimodal analgesia for bariatric surgery.39Further demonstration of this technique in bariatric populations was shown by Mulier and colleagues in a randomized controlled trial of 43 patients examining postoperative opioid consumption and quality of recovery in opioid versus opioid-free treatment arms.40 Patients in the opioid-free treatment group were administered loading doses of dexmedetomidine, ketamine, and lidocaine before induction and maintained on lidocaine and dexmedetomidine infusions. Patients in the opioid treatment group were administered sufentanil before induction and maintained on a sufentanil infusion. Both treatment groups received propofol, rocuronium, and sevoflurane titrated to BIS 40 to 60. Postoperative analgesic regimens were the same in both treatment groups and included scheduled paracetamol and a morphine patient-controlled analgesia (PCA) pump. Patients in the opioid-free treatment group were found to have a statistically significant higher quality of recovery as measured by the QoR-40 questionnaire the morning after surgery. The incidence of PONV and shivering were also significantly lower in the opioid-free group. Total morphine consumption was lower for opioid-free patients during their PACU stay, but there was no difference in total morphine consumption 24 hours postoperatively.40 Although the study had a small sample size, the results appeared consistent with other opioid-free techniques. The equal levels of morphine consumption postoperatively do not seem to suggest superiority or inferiority of either technique, but may suggest a need to revise how postoperative analgesic regimens are designed. A randomized controlled trial in 119 bariatric patients examined rates of PONV in patients receiving either opioid-free total IV anesthetics (TIVA) or traditional volatile-opioid anesthesia. Opioid-free treatment groups received TIVA with a loading dose of dexmedetomidine and a maintenance infusion of dexmedetomidine, propofol titrated to BIS 40 to 60, and a single bolus dose of ketamine before incision. Opioid treatment groups received fentanyl before induction and intermittent bolus dosing of either fentanyl, morphine, or hydromorphone during the procedure with volatile anesthetics at a minimum alveolar concentration of 0.7 to 1.3 for maintenance of anesthesia. The authors found a 17.3% absolute risk reduction of PONV in patients receiving opioid-free anesthetics compared with the classic opioid treatment groups.41 Laparoscopic cholecystectomy A randomized controlled trial of 80 patients undergoing elective laparoscopic cholecystectomy evaluated postoperative opioid requirements and PONV in groups treated with opioid-free TIVA versus opioid-containing TIVA. Opioid-free groups received loading doses of dexmedetomidine and lidocaine, followed by infusions of dexmedetomidine, lidocaine, and propofol. Opioid-containing groups received a fentanyl (2 mcg/kg) bolus dose, followed by infusions of remifentanil and propofol. The investigators found that the opioid-free treatment group had significantly more hypertensive episodes requiring treatment and the opioid-containing group had significantly more hypotensive episodes requiring treatment. None of the patients in the opioid-free group required treatment for PONV postoperatively, representing a statistically significant difference between groups. Postoperative fentanyl consumption was significantly lower for the opioid-free group at the 2-hour postextubation time point, but cumulative opioid consumption at the 4-hour and 6-hour postextubation time points was similar between both groups. PACU discharge times were significantly longer in the opioid-free groups and after discharge to the surgical ward, the opioid-free group showed significantly lower pain scores and lower need for rescue analgesics.42 In terms of longer PACU stays after intraoperative dexmedetomidine infusions, we again encounter the question of whether the opioid-sparing effects of dexmedetomidine are robust or are related to increased postoperative sedation, an idea that needs to be further explored. Hysterectomy Blanton and colleagues performed a systematic review investigating nonopioid pharmacologic interventions in the setting of minimally invasive hysterectomies.43 Postoperative analgesic consumption and postoperative pain scores were the primary outcomes examined. Interventions included local anesthetic wound infiltration, transversus abdominis plane block, paracervical block, gabapentinoids, IV acetaminophen, ketorolac, dexamethasone, nefopam, and dexmedetomidine. Of the interventions used, paracervical block, gabapentinoids, IV acetaminophen, ketorolac, dexamethasone, and nefopam showed significant postoperative opioid-reducing effects. Improvements in pain scores were only found to be significant for paracervical block and NSAIDs at early postoperative time points and were no longer significant past the 24-hour time point. Subcutaneous and intraperitoneal instillation of local anesthetic, transversus abdominis plane blocks, and dexmedetomidine failed to provide any significant benefit.43 Variations in the effectiveness of multimodal analgesic agents and regional blocks observed with specific surgical procedures highlight the importance of further study into procedure-specific effectiveness that may allow for the refinement of opioid-free and opioid-sparing techniques. Enhanced recovery after surgery (ERAS) Chronic opioid use commonly begins with excessive prescriptions for acute pain control. Further, it has been suggested that greater opioid consumption during an inpatient stay is associated with greater use of opioids after discharge.44 ERAS pathways are a promising vehicle to integrate opioid-sparing or opioid-free protocols into clinical practice. The foundations of these protocols are tailored around multimodal nonopioid analgesic regimens. These regimens typically begin in the preoperative period with a combination of acetaminophen, an NSAID, and a gabapentinoid, as long as there are no contraindications. This is followed by intraoperative use of regional anesthetic techniques whenever applicable and continuation of a multimodal analgesic pain regimen through to the postoperative period with scheduled acetaminophen, NSAIDs, and gabapentinoids. Breakthrough pain is then managed with judicious use of opioid analgesics to complete the multimodal pain pathway.9 Brandal and colleagues found that implementation of an ERAS protocol for colorectal surgery led to a significant increase in multimodal analgesic techniques and a significant decrease in the amount of intraoperative opioid administered. However, over 80% of patients studied were prescribed an opioid analgesic at discharge, even in a large majority of patients who reported low discharge pain scores, low opioid consumption before discharge, and no preoperative opioid use. This finding reinforces the idea that even with successful implementation of an ERAS protocol, physician behavior and discharge prescribing practices remain important targets to promote the success of opioid-free and opioid-sparing techniques.44 Campsen and colleagues conducted a randomized controlled trial examining the effectiveness of an opioid-free ERAS protocol using pregabalin and ketorolac in live donor nephrectomies. The study found significant reductions in length of stay and opioid consumption in the opioid-free group without any significant increase in complications.45 A retrospective review examining an enhanced recovery protocol versus routine perioperative care in 100 patients undergoing hemiarthroplasty for femoral neck fracture showed a decrease in oral opioid consumption during the first three postoperative days in the group on the ERAS pathway. The ERAS patients also showed a reduction in use of PCA. There was no significant difference in the time to discharge between the 2 groups, but ERAS patients were more likely to be discharged to their homes as opposed to rehabilitation centers or community care centers.46 Warren and colleagues showed that implementation of an ERAS protocol focused on multimodal analgesia in ventral hernia repair nearly eliminated postoperative PCA use and significantly reduced opioid requirements during the first 3 postoperative days. The results were also consistent with patients receiving simultaneous epidural analgesia. The ERAS protocol used intraoperative ketamine and lidocaine infusions and a postoperative ketamine infusion, ketorolac, and acetaminophen.47 Pediatric opioid-free and opioid-sparing anesthesia Pediatric populations appear to benefit from many of the same multimodal analgesic approaches as adult patients, although there is a paucity of trial data specific to pediatric drug dosing for opioid-free and opioid-sparing anesthetic techniques. Among the available evidence, acetaminophen, NSAIDs, dexamethasone, ketamine, clonidine, and dexmedetomidine have been shown to decrease postoperative opioid consumption and improve pain scores in pediatric populations. Further research is required to understand the effectiveness of gabapentinoids, magnesium, lidocaine, and esmolol.48 Conclusion Anesthesiologists have long played a critical role in the management of perioperative pain. Deciding how to treat pain in the perioperative period appears to have further-reaching implications than it would in the initial recovery phase. As we enter the third decade of the opioid epidemic in the United States, it is becoming more important than ever to reevaluate our practice of pain management in the perioperative setting. Opioid-free intraoperative protocols have been successfully used in specific surgical populations with equal or superior results to classic general anesthetic approaches. In instances where opioid-free anesthesia may not be entirely feasible, there exists a continually growing body of evidence that the modern anesthesiologist has a potent pharmacologic and regional anesthetic arsenal that can reduce the amount of opioids required to effectively treat pain. There was a period of time in our practice when it appeared that the anesthesiologist of the day could not imagine a practical alternative to open drop ether. Ether had many favorable properties, but it eventually gave way to safer anesthetic techniques. We are practicing in a time of tremendously improved safety and efficiency, which was a product of a deliberate movement away from established norms. It has been nearly a century since the introduction of the original "balanced anesthetic," and although the principles may still be relevant, our tools and knowledge have grown and evolved. As we find more compelling reasons to change the way we use opioids in the practice of anesthesia, it may be time to explore alternatives to the things that we currently view as standard. Conflicts of interest and source of funding T.S.M. has received grant funding from Merck. E.Y.S. declares that there is nothing to disclose.