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 and 24-hour time pain scores at hours postoperatively were not significantly Patients treated with lidocaine also showed significantly decreased postoperative opioid consumption during the first 48 hours postoperatively and decreased time to first and bowel Similarly, a trial examining the effect of IV lidocaine on recovery in laparoscopic cholecystectomy showed significantly reduced pain intensity for to hours postoperatively, reduced opioid consumption to 24 hours postoperatively, and decreased time to first and bowel In addition, serum concentrations of and were at the of the and hours postoperatively and patients showed less multiple mechanisms of action in mitigating surgical The of as an anesthetic agent was first described in the literature in et described the of the of to lower the for in through which results in sympatholysis, and a mechanism of modulation of was for clinical use by the in mechanism has been as an inhibition of the that leads to of in increased This leads to inhibition of the which is responsible for the of sedation to eye movement IV has been shown to produce significantly decreased postoperative pain scores, increased opioid-free time in the and opioid-sparing effects for to 24 hours postoperatively compared with placebo and However, prolonged PACU have also been seen with in randomized controlled Further, patients have shown an increased time to emergence from anesthesia, which the question of whether postoperative sedation could the increased opioid-free et this using a and showed that the increased opioid-free and lower opioid were despite the emergence times and PACU still be to the potential effects of and dosage be considered with administration in With respect to other side effects, and are common concerns with typically occurs at higher plasma concentrations such as those achieved with bolus administration and way to with in plasma treatment has been consistent across many and to be by the method of with bolus administration higher for compared with Despite the increased incidence of significant in the risk of active treatment have not been is a synthetic with high that has been used to reduce PONV and postoperative However, it has also shown potential in postoperative pain and reducing discharge times from surgery A meta-analysis examining the effects of perioperative on postoperative analgesia showed significantly pain scores, an opioid-sparing effect at 2 and 24 and reduced PACU Study doses of ranged from 4 to with the most common dosage 8 There was no evidence of a effect on opioid requirements and a small but significant effect on 24-hour pain results were found in patients receiving during laparoscopic Patients reported lower postoperative analgesic requirements and a reduced length of compared with In the same was also shown to significantly improve pain scores, nausea, and as reported by the QoR-40 Despite its many also carries significant side effects. concerns with routine use of include perioperative postoperative and effects ranging from to does appear to be a common during postoperative and be with administration to diabetic However, there does not appear to be evidence an increased incidence of postoperative or with opioid-sparing doses of intraoperative anesthetic techniques anesthesia has demonstrated recovery both when compared with and used in with In ambulatory procedures, regional anesthetics have shown lower postoperative pain scores, PACU discharge and a lower incidence of PONV than patients receiving The of regional anesthetics in opioid-free and opioid-sparing was in a study that examined patients who received and lower peripheral nerve for ambulatory surgical The study demonstrated that about of patients to the PACU with pain and did not opioid in the A further in opioid-free and opioid-sparing is pain control after patients the pain after surgery can a significant A meta-analysis examined the effect of regional anesthetic techniques on the incidence of postoperative pain, as pain after surgery. It was that by central regional anesthetic techniques could improve pain outcomes. The found that regional anesthesia used in and showed significant in patient risk of postoperative pain compared with results show the potential for regional anesthetic techniques to an role in the management of perioperative pain. is often on and reducing acute pain in the postoperative but postoperative chronic pain are also major to opioid anesthesia may as a route to reduce the of postoperative pain. Opioid-free surgery of the most opioid-free have been used in the of bariatric surgery. Patients undergoing bariatric surgery often from obstructive sleep apnea and are at a high risk for from opioid-related side effects. and colleagues reported an opioid-free protocol that a multimodal analgesic regimen Ketamine mg/kg magnesium mg/kg lidocaine mg/kg and were administered as bolus doses at the of anesthesia, with the of which was administered at 10 before The analgesic medications were during the as infusions until the of the with the of ketamine, which was 30 before the of the to potential psychotomimetic side effects. and were achieved with and and was achieved with to a of to and were administered for PONV and acetaminophen and NSAIDs were also administered at the of the With a protocol in the setting of a the were able to a reliable anesthetic with or no 1: and dosing of multimodal analgesia for bariatric of this technique in bariatric was shown by and colleagues in a randomized controlled trial of patients examining postoperative opioid consumption and quality of recovery in opioid versus opioid-free treatment Patients in the opioid-free treatment were administered doses of ketamine, and lidocaine before and on lidocaine and Patients in the opioid treatment were administered before and on a Both treatment groups received and to to analgesic were the same in both treatment groups and included and a morphine analgesia Patients in the opioid-free treatment were found to have a significant higher quality of recovery as by the QoR-40 the after surgery. The incidence of PONV and were also significantly lower in the opioid-free morphine consumption was lower for opioid-free patients during their PACU stay, but there was no difference in morphine consumption 24 hours Although the study had a small the results consistent with other opioid-free The equal levels of morphine consumption postoperatively not to superiority or of either but may a to postoperative analgesic are A randomized controlled trial in bariatric patients examined rates of PONV in patients receiving either opioid-free IV anesthetics or Opioid-free treatment groups received with a dose of and a infusion of to to and a single bolus dose of ketamine before incision. treatment groups received fentanyl before and bolus dosing of either or during the with anesthetics at a concentration of to for of The found a risk reduction of PONV in patients receiving opioid-free anesthetics compared with the opioid treatment cholecystectomy A randomized controlled trial of patients undergoing laparoscopic cholecystectomy evaluated postoperative opioid requirements and PONV in groups treated with opioid-free versus Opioid-free groups received doses of and followed by infusions of and groups received a fentanyl bolus followed by infusions of and The found that the opioid-free treatment had significantly more treatment and the had significantly more of the patients in the opioid-free required treatment for PONV postoperatively, a significant difference between fentanyl consumption was significantly lower for the opioid-free at the time but opioid consumption at the and time points was similar between both PACU discharge times were significantly in the opioid-free groups and after discharge to the surgical the opioid-free showed significantly lower pain scores and lower for In terms of PACU after intraoperative infusions, the question of whether the opioid-sparing effects of are or are related to increased postoperative an idea that to be further and colleagues a systematic review nonopioid pharmacologic in the setting of analgesic consumption and postoperative pain scores were the primary outcomes included local anesthetic IV acetaminophen, and the IV acetaminophen, and showed significant postoperative effects. in pain scores were found to be significant for block and NSAIDs at early postoperative time points and were no significant the 24-hour time point. and of local anesthetic, and failed to significant in the effectiveness of multimodal analgesic agents and regional with surgical the of further study into effectiveness that may for the of opioid-free and opioid-sparing recovery after surgery opioid use commonly with for acute pain Further, it has been suggested that greater opioid consumption during an is associated with greater use of opioids after are a promising vehicle to opioid-sparing or opioid-free into clinical The of these are multimodal nonopioid analgesic regimens. typically in the preoperative period with a of acetaminophen, an and a as long as there are no This is followed by intraoperative use of regional anesthetic techniques and of a multimodal analgesic pain regimen through to the postoperative period with acetaminophen, and pain is with use of opioid to the multimodal pain and colleagues found that of an protocol for colorectal surgery led to a significant increase in multimodal analgesic techniques and a significant decrease in the of intraoperative opioid However, over of patients were an opioid analgesic at even in a large majority of patients who reported low discharge pain scores, low opioid consumption before and no preoperative opioid This the idea that even with of an and discharge prescribing important to the of opioid-free and opioid-sparing and colleagues a randomized controlled trial examining the effectiveness of an opioid-free protocol using pregabalin and ketorolac in The study found significant in length of and opioid consumption in the opioid-free without significant increase in A review examining an recovery protocol versus routine perioperative care in patients undergoing for showed a decrease in oral opioid consumption during the first postoperative in the on the The patients also showed a reduction in use of There was no significant difference in the time to discharge between the 2 but patients were more to be discharged to their as opposed to or care and colleagues showed that of an protocol on multimodal analgesia in postoperative use and significantly reduced opioid requirements during the first postoperative The results were also consistent with patients receiving analgesia. The protocol used intraoperative ketamine and lidocaine infusions and a postoperative ketamine and opioid-free and opioid-sparing anesthesia appear to benefit from many of the same multimodal analgesic as there is a of trial to drug dosing for opioid-free and opioid-sparing anesthetic the acetaminophen, ketamine, and have been shown to decrease postoperative opioid consumption and improve pain scores in populations. is required to the effectiveness of magnesium, and have long a role in the management of perioperative pain. to pain in the perioperative period to have than it would in the recovery As the of the opioid epidemic in the United it is more important than to practice of pain management in the perioperative Opioid-free intraoperative have been used in surgical with equal or results to anesthetic In where opioid-free anesthesia may not be there exists a of evidence that the modern anesthesiologist has a pharmacologic and regional anesthetic that can reduce the of opioids required to pain. There was a period of time in practice when it that the anesthesiologist of the could not a to had many favorable properties, but it eventually way to anesthetic are in a time of and which was a of a movement from established It has been a since the introduction of the "balanced and the may still be and have and As more to the way use opioids in the practice of anesthesia, it may be time to to the that currently as of and of has received from that there is to