Opioid-free and opioid-sparing anesthesia

Abstract

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 significant difference in scores at 24 hours after surgery and significant difference in time to of PACU pain scores, or opioid analgesic requirements in the exists as the most common and the most common plasma It has a wide of effects on the of and In the clinical setting, is typically used as an and Although not commonly as an analgesic has also been shown to act as an NMDA receptor This in addition to its as a calcium to its potential as an analgesic A meta-analysis the effectiveness of IV as an analgesic significant effects, reducing postoperative opioid consumption and early to and late pain Early pain with movement to was not reduced with but late pain with movement was administration across the studies in the meta-analysis used bolus doses from to mg/kg, by at rates from to remains a concern with but reports of clinical were found the study In addition to its opioid-sparing has been shown to hemodynamic stability intraoperatively. and examined the of IV in hemodynamic to A meta-analysis showed that significantly reduced rate compared with but there was effect on Although rate stability is associated with under anesthesia, it is to rate stability was due to the effects of or it was a effect of the effect of and are of to function through binding to of voltage-dependent sodium in at these receptors has been found to the of and central has been for use in the treatment of chronic pain from and complex regional pain Although and are used for an analgesic and opioid-sparing their clinical effectiveness A meta-analysis of postoperative pain in patients versus placebo showed that perioperative administration of did not significantly reduce pain intensity in the first 24 hours after The show that significantly reduced opioid consumption during the period. Patients also had a lower incidence of but an incidence of to reduce pain has shown more promising clinical A review by et examining the of in acute postoperative pain management that preoperative administration of was in reducing both pain scores and opioid Similarly, a meta-analysis by and colleagues showed a significant decrease in pain scores during the first hours and at 24 hours in patients treated with preoperative A decrease in postoperative opioid was also found in patients versus of across studies most from to mg and were administered as a single dose 1 to 2 hours before With respect to common side effects, there did not to be a consistent decrease in of nausea, or across There to be a significantly incidence of postoperative in patients local IV use of local such as and for has been reported in the literature since the mechanisms for local pain have of pain at the of the spinal and a reduction in the of peripheral The concentration of for has been at 2 to in which reduces from and In it has been that used at plasma concentrations to sodium is still to the of inflammatory and act as an NMDA receptor The of for postoperative pain management in surgery was examined by a meta-analysis with a decreased postoperative pain scores were at and 24-hour time pain scores at hours were not significantly Patients treated with also showed significantly decreased postoperative opioid consumption during the first 48 hours and decreased time to first and bowel Similarly, a trial examining the effect of IV 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 concentrations of and were at the of the and hours and patients showed less multiple mechanisms of action in 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 to of in This to inhibition of the which is responsible for the of to movement IV has been shown to produce significantly decreased postoperative pain scores, opioid-free time in the and opioid-sparing effects for to 24 hours compared with placebo and However, PACU have also been with in randomized controlled Further, patients have shown an time to emergence from anesthesia, which the question of postoperative could the opioid-free et this using a and showed that the opioid-free and lower opioid were the emergence times and PACU still be to the potential effects of and dosage be with administration in With respect to other side effects, and are common concerns with typically occurs at 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 for compared with Despite the incidence of significant in the risk of 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 times from surgery A meta-analysis examining the effects of perioperative on postoperative showed significantly pain scores, an opioid-sparing effect at 2 and 24 and reduced PACU Study doses of from to with the most common dosage There was evidence of a effect on opioid requirements and a small but significant effect on 24-hour pain results were found in patients during laparoscopic Patients reported lower postoperative analgesic requirements and a reduced of compared with In the was also shown to significantly pain scores, nausea, and as reported by the Despite its many also carries significant side effects. concerns with routine use of include perioperative postoperative and effects from to does to be a common during postoperative and be with administration to However, there does not to be evidence an 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 have shown lower postoperative pain scores, PACU and a lower incidence of PONV than patients The of regional in opioid-free and opioid-sparing was in a study that examined patients who received and lower peripheral 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 It was that by central regional anesthetic techniques could pain 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 in the management of perioperative pain. is on and reducing acute pain in the postoperative but postoperative chronic pain are also 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 Patients undergoing bariatric surgery 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 mg/kg mg/kg and were administered as bolus doses at the of anesthesia, with the of which was administered at before The analgesic medications were during the as until the of the with the of ketamine, which was 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 to a reliable anesthetic with or 1: and dosing of multimodal 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 before and on and Patients in the opioid treatment were administered before and on a Both treatment groups received and to to analgesic were the in both treatment groups and and a morphine Patients in the opioid-free treatment were found to have a significant quality of recovery as by the the after The incidence of PONV and were also significantly lower in the opioid-free morphine consumption was lower for opioid-free patients during their PACU but there was 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 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 either opioid-free IV 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 at a concentration of to for of The found a risk reduction of PONV in patients opioid-free 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 by of and groups received a fentanyl bolus by 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 times were significantly in the opioid-free groups and after to the surgical the opioid-free showed significantly lower pain scores and lower for In terms of PACU after intraoperative the question of the opioid-sparing effects of are or are related to postoperative an idea that to be further and colleagues a review nonopioid pharmacologic in the setting of analgesic consumption and postoperative pain scores were the primary outcomes local anesthetic IV acetaminophen, and the IV acetaminophen, and showed significant postoperative effects. in pain scores were found to be significant for and NSAIDs at early postoperative time points and were significant the 24-hour time point. and of local anesthetic, and 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 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 This is 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 pain scores, low opioid consumption before and preoperative opioid This the idea that even with of an and 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 and ketorolac in The study found significant in of and opioid consumption in the opioid-free 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 significant difference in the time to 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 in postoperative use and significantly reduced opioid requirements during the first postoperative The results were also consistent with patients analgesia. The protocol used intraoperative ketamine and and a postoperative ketamine and opioid-free and opioid-sparing anesthesia to benefit from many of the 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 pain scores in populations. is required to the effectiveness of and have long a 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 but it eventually way to anesthetic are in a time of and which was a of a movement from 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

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