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Novel analgesics in ambulatory surgical patients

Iskander, Andrew; Gan, Tong J.

Current Opinion in Anesthesiology: December 2018 - Volume 31 - Issue 6 - p 685–692
doi: 10.1097/ACO.0000000000000665
AMBULATORY ANESTHESIA: Edited by Claude Meistelman

Purpose of review The increasing number of procedures done in the ambulatory surgical setting necessitates the need for analgesic modalities that enable the management of postsurgical pain with fast onset, predictable duration of action, and minimal need for management of undesirable side-effects.

Recent findings The novel strategies for administration of local anesthetics in the ambulatory setting include prolonging their analgesic action at the site of surgical trauma while reducing systemic effects that result from their metabolism. Development of opioids aims to address receptor sites that provide for modulation of pain perception while reducing systemic, central effects of μ-receptor agonism. Other, more titratable agents with analgesic properties are also addressed.

Summary Local anesthetics, opioids, and NSAIDS are the mainstay of multimodal analgesic management, and as such, improving their efficacy in the ambulatory surgical setting remains the primary focus. However, as knowledge of the modulating pathways involved in transduction of pain increases, newer agents that utilize this knowledge are also becoming more widely available.

Department of Anesthesiology, Stony Brook University, Stony Brook, New York, USA

Correspondence to Tong J. Gan, MD, MBA, MHS, FRCA, Department of Anesthesiology, Stony Brook University, HSC Level 4, Rm 060, Stony Brook, NY 11794-8480, USA. Tel: +1 (631) 444 2907; e-mail:

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Enhanced recovery protocols (ERP) are strategies implemented with the intention of increasing the cost-effectiveness of surgical patient throughput, reducing surgical morbidity, and decrease length of stay [1]. The main principles include preoperative optimization, intraoperative strategies to maintain homeostasis, and postoperative care that addresses the most common sources of delay for discharge and indications for readmission. Successful ERP also result in an increase in cost-effectiveness and patient satisfaction [2,3,4▪,5,6▪▪,7]. These pathways seek to examine and prioritize factors involving preoperative patient education and nutrition, multimodal analgesia, appropriate monitoring of anesthetic depth, increased use of regional techniques, and postoperative strategies to avoid the need for treatment for postoperative complications, including rebound pain after the peripheral nerve block has worn off.

In the context of pain management, multimodal analgesia, defined as the use of multiple modalities and analgesic techniques for the effective management of intraoperative nociception and postoperative pain while reducing postoperative drug-related adverse events, is the cornerstone of an ERP. In this review, we discuss novel analgesics and formulations that may be incorporated into an ERP.

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Local anesthetics

The continued development and improvement of ultrasound technology has in the last two decades greatly increased safety and efficacy of administration of an enlarging repertoire of medications [8▪,9,10] in peripheral nerve blocks. The evidence in the literature has seen improvements in the types of needle administration systems, medications used, and nerve stimulation techniques. However, the use of continuous catheter techniques are themselves subject to a number of complications including nerve and vascular injury, failure of the block, and infection that have led to research in improving the drugs used for local infiltration and perineural injections. By enhancing the efficacy of the medications used for single-shot local and perineural injection, the inherent complications with their use in the ambulatory setting can be mitigated. This enables practitioners to utilize the local effects of these drugs while reducing the systemic effects. We discuss novel injectable drug delivery formulations of analgesics using nanoparticles, the current state of use of injected depot delivery systems of local anesthetics, and the combination product of a local anesthetic with an NSAID.

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Nanoparticle delivery systems

In recent years, the use of nanoparticles has garnered a great deal of interest [11▪,12▪,13–15]. Nanoparticle formulations result from the need to address the pharmacokinetic reality of administering local anesthetics, that is, they have short duration of action [16–18], usually on the order of minutes. By encapsulating the local anesthetic, the local degradation of the drug bolus can be delayed until the desired effect and duration is achieved.

In an effort to address some of these shortcomings utilizing a nanosphere delivery system, Mantha et al. [19] studied the use of ropivicaine-associated magnetic nanoparticles in a rat ankle block model. Their aim was to examine if ropivacaine-complexed magnetic nanoparticles could be directed to the ankle of interest by using a magnet applied to the ankle. Tissue surrounding the ankle was sampled at the time of injection and 30 min after. Blood samples at various timepoints were drawn to examine the plasma concentrations of the ropivicaine complexes. Interestingly, they observed that the drug release profile was such that at 30 min, magnet application was more effective than 15 or 60 min of application in effecting discernable anesthesia. Furthermore, they found that the plasma concentration of the complexed ropivicaine was several-fold higher than directly injecting the drug. This enabled the ropivicaine to be targeted to the desired location, in the desired time frame, thus resulting in better analgesia with less systemic toxicity.

With the increase in the study and development of nanoparticle delivery systems, there has been increased attention paid to their possible cytotoxicity [20–22]. In the study by Toropova [23], the in-vitro toxicity of magnetic nanoparticles in human umiblical vein endothelial cells was examined. Significantly, dose-dependent changes were seen in morphology and rate of apoptosis. Furthermore, at higher doses, the nanoparticles increased the population of binucleated cells, which the authors suggest resulted from impaired cytokinesis. To further support the association between the nanoparticles and altered cell division, deposits of the nanoparticles were predominantly found in those cells with binucleated cells. This suggests that nanoparticles continue to have a significant association with cytotoxicity, in vitro.

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Depot delivery systems

Depot delivery of local anesthetics is an area which has received much interest with a number of formulations in various stages of clinical development [24–37]. These include liposomal bupivacaine (depobupivacaine), SABER-bupivacaine, bupivacaine collagen matrix, and HTX-011, a combination product of bupivacaine and meloxicam.

Depobupivacaine utilizes the DepoFoam technology developed by Pacira Pharmaceuticals, Inc (Parsippany, New Jersey, USA). By encompassing the local anesthetic in a DepoFoam particle composed of groups of lipid bilayer vesicles, the metabolism of the drug is controlled to prolong its activity after local or perineural injection [38,39]. In a retrospective case series [40], the investigators found that intraoperative injection of liposomal bupivacaine during palatoplasty results in decreased opioid usage in the immediate postoperative period and increased patient comfort leading to increased postoperative fluid intake. Of note, the patients had an average age of 10 months. In 2017, a double-masked, randomized clinical trial demonstrated that women who underwent preincision infiltration with liposomal bupivacaine [41] reported less pain postoperatively when compared with the cohort who received 0.25% bupivacaine. Bromberg et al. [25], in a literature review, observe that depobupivacaine may have apparent benefits in the ambulatory setting when compared to conventional formulations, but it is less clear that cost is better with its use over conventional bupivacaine. However, the cost savings apparent in the use of liposomal local anesthetics was shown by Wang et al. [37] when they compared liposomal bupivacaine versus ropivacaine pain ball in adductor canal block. Though the mean pain scores were ultimately similar, the liposomal bupivacaine group after total knee arthroplasty had a distinct direct and total cost savings in the liposomal bupivacaine group.

Recently, there has been work by other investigators [42▪▪,43,44] in which they describe the possible use of ultrasound and liposomes theorized to allow for localized control of tetrodotoxin administration at a target site. The ultrasound energy applied would increase the transport of hydrophilic liposomal molecules through tissue barriers until the neural surface was reached. By utilizing acoustic cavitation (formation of bubbles using targeted ultrasound energy), the local anesthetic is released only at the desired time and target in otherwise stable liposomes. The use of liposomes for delivery of local anesthetics deserves further study as the use of ultrasound may enhance delivery to a desired site, but it is unclear whether the potentially lethal systemic effects are mitigated. However, Ahmadi et al. [45] argues that delivery of high-frequency ultrasound, which may be safer for perineural drug delivery than the lower frequency ultrasound, may not be efficacious in enhancing delivery of drugs to larger nerves like the sciatic nerve that are common targets for nerve blockade.

SABER-Bupivacaine, developed by Durect Corp. (Cupertino, California, USA), also aims to prolong the effects of bupivacaine [46]. This formulation contains an esterified sugar matrix, sucrose acetate isobutyrate and benzyl alcohol, which prolongs the effects for up to 72 h postinjection. In a double-blinded RCT by Hadj et al. [47], SABER bupivacaine was studied for use in open-hernia repair. The patients were randomized to receive either 2.5 or 5 ml of SABER-Bupivacaine, or SABER-placebo at the time of wound closure. In patients who received the 5 ml solution of the SABER-Bupivacaine, there was a reduction in the number of patients who required additional opioids.

Another formulation that aims to prolong the local anesthetic effect incorporates bupivacaine in a collagen matrix (Innocoll, Newtown Square, Pennsylvania, USA). Using a collagen-based technology platform, bupivacaine is paired with collagen in a bioresorbable implant inserted at the surgical incision site and slowly emits the bupivacaine in a controlled fashion. In two phase 3 studies (MATRIX-1 and MATRIX-2), the implant was compared with placebo and demonstrates statistical significance for reduction in pain intensity scores for 24 h (SPID-24). At 72 h, there was a trend toward a reduction of the SPID, though not statistically significant. However, the result was statistically significant when the SPID-72 data of the two studies were pooled. There was a reduction in the incidence of opioid-related adverse events when compared to the placebo group. This formulation is awaiting FDA approval.

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Local anesthetics with an NSAID

A local anesthetic and an NSAID are commonly administered as part of the multimodal pain management strategy. A novel compound being investigated incorporates depo-bupivacaine and meloxicam, a commonly used NSAID. In two randomized, controlled, double-blinded studies, HTX-011 (Heron Therapeutics, San Diego, California, USA), was shown to reduce pain intensity and the need for opioid analgesic rescue. The addition of an NSAID in this case is thought to reduce the local incisional edema and reduce the local on-site acidity typical with tissue damage, hence potentially increase the effectiveness of the local anesthetic. In these studies (EPOCH 1 studied bunionectomy patients and EPOCH 2 used a cohort of hernia repair patients), the pain intensity area under the curve (AUC) was reduced significantly when compared to patients who received bupivacaine-only solution or placebo for 72 h after surgery. Furthermore, there was a decrease in the need for rescue analgesia and an increase in the number of patients who did not require opiates at all. It is awaiting approval from the FDA.

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Systemic pharmacologic agents

Another space in which advancements have been made in ambulatory analgesia includes the synthesis of novel opioids and opioid delivery systems. This is important in the current era of epidemic of opioid dependence in the United States. Despite this, in 2017, over half of all ambulatory surgical patients received a prescription for an opioid postoperatively [48▪]. This is likely in part because of the increasing complexity of the procedures that are performed on an outpatient basis, as well as the perceived expectation from the patients for an opioid prescription.

In the context of a multimodal analgesia model, one of the benefits of moving away from opioid monotherapy is the hope of trying to reduce the chance that patients will suffer from opioid dependence. This results from the fact that morbidity surrounding opioid dependence is a consequence of the characteristic pharmacodynamics profile of opioids most used today – namely, a narrow therapeutic window with a broad side-effect profile. We will discuss newly developed systemic therapies and novel administration strategies of conventional drugs that aim to address these shortcomings including a novel, centrally acting μ-receptor agonist noradrenaline reuptake inhibitor, tapentadol; a novel G-protein-biased μ-receptor analgesic, oliceridine; a novel κ-receptor agonist, CR-845 or difelikafelin; sufentanil microtablets that can be administered via the sublingual route; inhaled fentanyl; and intranasal and slow-release dexmedetomidine.

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Tapentadol is considered the first in a new class of analgesics that act synergistically as an agonist at the μ-opioid receptor and noradrenaline reuptake inhibitor. Thus, the MOR-NRI designation to describe a new class meant to be used in the setting of acute perioperative pain and more chronic neuropathic pain. The synergy allows for analgesic effects comparable to conventional opioids. However, as a result of a nearly 50-fold lower affinity for the mu receptor compared to morphine, there appears to be a more favorable side-effect profile, including less postoperative nausea vomitting (PONV) and less abuse potential, and respiratory depression at lower doses [49,50]. In a comparative study of patients undergoing third molar mandibular surgery [51], tapentadol demonstrated analgesic efficacy comparable to ketorolac at different time points up to 3 days postsurgery. In a randomized, double-blind, placebo controlled phase 3 clinical trial [52] in patients undergoing bunionectomy, tapentadol was shown to be comparable to oxycodone for analgesic efficacy with reduced incidence of nausea and vomiting.

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Conventional opioids provide powerful analgesia in the acute pain setting, but also produce efficacy-limiting adverse effects, such as severe nausea, vomiting, and potentially life-threatening respiratory depression. Both analgesia and adverse effects of conventional opioids are mediated by the μ opioid receptor, leading to the assumption that these effects are inseparable. Oliceridine is a drug that has a new mechanism of action compared to conventional opioid. It is referred to as a biased agonist, with [53,54] μ-receptor activation via preferential G-protein pathway versus the β-arrestin activation, thereby allowing for antinociception with fewer untoward side effects (Figs 1 and 2).





In a randomized phase IIb study [55], cohorts of patients undergoing abdominoplasties were grouped into treatment groups with two different oliceridine loading doses, different patient-controlled analgesia (PCA) doses, morphine, and placebo regimens. The reduction in pain scores of the oliceridine groups was similar to the morphine group, with a decreased incidence of nausea, vomiting, and clinically determined respiratory depression. Pharmocokinetic studies demonstrate that the dose response is predictable and demonstrated covariates of weight, and CYP2D6 status [56▪▪]. The effect of body weight appeared to be more significant than sex, as the AUC of total exposure to the drug diminished with decreased body weight, and this effect seemed largely unaffected by sex. Oliceridine is metabolized by CYP3A4 and 2D6. In the CYP2D6-PM group (“poor-metabolizers”, the clearance was half of the CYP2D6-EM group (“extensive metabolizers”).

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In the ambulatory surgical setting, it is beneficial to have the analgesic efficacy of opioids, whereas minimizing or eliminating the conventional opioid side effects that often result in prolongation of PACU stay or readmission. Difelikefalin or CR-845 (Cara Therapeutics, Stamford, Connecticut, USA), is a κ-receptor agonist. By avoiding the conventional μ-receptor group, the incidence of the central side effects of opioid agonism are mitigated.

The κ receptors are agonized at the peripheral nerves, avoiding undesirable effects leading to increased healthcare interventions and abuse potential such as respiratory depression, nausea and vomiting, and euphoria. In completed phase 2 trials (, the CR-845 group resulted in a statistically significant reduction in pain intensity as measured by AUC utilizing the numerical rating scale collected over the first 24 h postop in patients who underwent inguinal hernia surgery and hysterectomy. Interestingly, there was also a statistically significant reduction in the incidence of PONV, need for rescue pain medication, and improvement in patient global assessment 24 h after surgery versus placebo. Adverse events including aquaresis (the diuretic loss of free water without electrolyte loss) in a dose-dependent fashion were observed. It is currently undergoing phase 3 trials.

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Sufentanil microtablets

To further examine ways to find analgesic treatments that can be used on outpatient basis, sufentanil has garnered attention because it has rapid equilibration between the plasma and CNS, on the order of just several minutes. This allows for greater titratability with quicker onset and longer duration of action, without the need for intravenous access, thereby facilitating use in an outpatient setting. In a dose-finding study by Singla et al. [57▪] in bunionectomy patients, sublingual sufentanil (Zalviso) when administered as a onetime 30 mcg dose had a significant prolongation on time to first rescue analgesic when compared with morphine, with fewer adverse events. A manufacturer programmed dispenser of 15 mcg nanotablets with a 20 min lockout was studied by Scardino et al. [58], where patients who underwent total knee replacements were placed on a fast-track program that utilized a multimodal analgesic regimen. They found that the patients with the conventional femoral nerve block-based regimen reported lower pain scores throughout the 3 day study period; the group whose pain was treated by sublingual fentanyl reported lower movement-evoked pain scores throughout the same test period. Of note, by taking the programming away from the caregivers and patients, the Zalviso dispenser device (AcelRx Pharmaceuticals, Redwood City, California, USA) appears to avoid a number of issues relating to abuse and overdose.

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Inhaled fentanyl administration

Of the opioid drugs studied, inhaled fentanyl appears to be the most consistent in terms of bioavailability. The Staccato Fentanyl for Inhalation device (Alexza Pharmaceuticals Inc., Mountain View, California, USA) was demonstrated by Macleod et al. [59] to provide similar peak arterial concentrations of fentanyl for inhaled and intravenous administration. Similar to the sublingual sufentanil administration, this provided a potential means by which opioids can be administered in a controlled manner, without the need for intravenous access. Intranasal fentanyl has been studied in the setting of procedural sedation in the emergency department setting. [60▪,61]. In a prospective, randomized, single-blind noninferiority trial, intranasal fentanyl was shown to be superior to intravenous (i.v.) morphine in reducing pain and distress during bedside incision and drainage procedures as measured by the Observational Scale of Behavioral Distress-Revised (OSBD-R) scores. However, this study was small, and therefore of limited clinical utility. Interestingly, in a study that relied on a questionnaire of woman who received intranasal fentanyl versus subcutaneous fentanyl or intramuscular pethidine for labor analgesia, the women who received intranasal fentanyl had the highest satisfaction scores. In fact, some were quoted as stating they would choose to deliver in a center that provided it over the other routes of administration [62].

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Apha-2 agonists

The utilization of older drugs which found some use for analgesia has included the α-2 agonist family of drugs. α-2 adrenergic receptors are thought to lie in the locus coeruleus , thereby reducing neural throughput along the posterior horn of the spinal cord. There are also α-2 receptors placed presynaptically, inhibiting release of norepinephrine thereby, inhibiting pain signal transmission in the brain. Dexmedetomidine, particularly, is thought to promote the release of acetylcholine along spinal internuerons, possibly contributing to the release of nitric oxide, which may help modulate analgesia. The use of intranasal dexmedetomidine is supported in the literature for use in pediatric sedation and analgesia [63]. For specific FDA approval for periprocedural pain, Dex-IN (RECRO Pharma, Malvern, Pennsylvania, USA) is a formulation that has undergone phase 2 testing. In a multicenter, double-blind, placebo-controlled study of patients who underwent bunionectomy, the study groups were allowed to receive either the intranasal dexmedetomidine or placebo every 6 h starting on postop day 1. Thus far, the drug has shown its potential efficacy as an analgesic as it demonstrated a significant summed pain intensity difference score after 48 h (SPID48) versus placebo. The study also noted the need for rescue analgesia, adverse events, and SPID48 scores over various times intervals. The adverse events included nasal discomfort, hypotension, and bradycardia.

A strategy of slow-release of dexmedetomidine has been tested via a transdermal patch. TPU-006 (Teikoku Pharma, San Jose, California, USA) is a transdermal system that is based on what has been used for transdermal lidocaine patches. It is intended to dispense the dexmedetomidine over 3 days when applied in the immediate postsurgical period. In a phase 2 double-blind proof-of-concept study, patients who underwent bunionectomy were given either test drug or placebo. The test group had lower pain scores, reduced need for opioid rescue over 3 days, and less constipation and nausea with no increase in sedation.

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Intravenous NSAIDS

Intravenous NSAIDS are an important element in the multimodal approach to ambulatory analgesia. The development of intravenous NSAIDS stems from their ability to address a number of sources of postsurgical morbidity at the same time with their analgesic, antipyretic, and anti-inflammatory effects [64]. Their opioid receptor-sparing effects lend themselves well to ambulatory surgery. Intravenous Ibuprofen, when given pre and postoperatively, has been shown to reduce pain scores and morphine use in patients who underwent orthopedic procedures [64]. Diclofenac suppositories, when administered with i.v. fentanyl PCA (in patients undergoing laminectomy surgery demonstrated higher satisfaction scores than those treated with i.v. acetaminophen and PCA [65]. In a randomized, controlled phase 2 study, Christensen et al. [66] reported that patients undergoing dental impaction surgery, i.v. meloxicam were compared against oral ibuprofen and placebo. The meloxicam group reported clinically meaningful reduction in pain scores as early as 10 min after dosing. The authors noted that the rapid onset of perceptible pain relief is important for the management pain in the ambulatory setting.

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The current and forthcoming strategies for analgesic management in the ambulatory setting employ two broad strategies: improving the analgesic effects of conventional medications that are already components of multimodal analgesic regimens using drug delivery vehicles that take advantage of established efficacy while trying to reduce their undesirable systemic side-effects and formulation of newer drugs that utilize the improved understanding of the intracellular pathways involved in pain transmission and modulation. As the metrics for determining efficacy of different analgesic regimens differ from one another, it may be challenging to develop direct comparisons in the context of ERP. Acceptance of specific accepted standards of efficacy may contribute to more direct comparisons and thus, greater conformity across different ambulatory analgesic protocols.

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Financial support and sponsorship


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Conflicts of interest

T.J.G., Advisory Board: Heron, Durect, Trevena.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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local anesthesia; NSAIDS; opioids

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