Optimizing Perioperative Use of Opioids: A Multimodal Approach

Abstract

Purpose of Review

The main purpose of this article is to review recent literature regarding multimodal analgesia medications, citing their recommended doses, efficacy, and side effects. The second part of this report will provide a description of drugs in different stages of development which have novel mechanisms with less side effects such as tolerance and addiction.

Recent Findings

Multimodal analgesia is a technique that facilitates perioperative pain management by employing two or more systemic analgesics along with regional anesthesia, when possible. Even though opioids and non-opioid analgesics remain the most common medication used for acute pain management after surgery, they have many undesirable side effects including the potential for misuse. Newer analgesics including peripheral acting opioids, nitric oxide inhibitors, calcitonin gene-related peptide receptor antagonists, interleukin-6 receptor antagonists and gene therapy are under intensive investigation.

Summary

A patient’s first exposure to opioids is often in the perioperative setting, a vulnerable time when multimodal therapy can play a large role in decreasing opioid exposure. Additionally, the current shift towards faster recovery times, fewer post-operative complications and improved cost-effectiveness during the perioperative period has made multimodal analgesia a central pillar of Enhanced Recovery After Surgery (ERAS) protocols.

Introduction

Poorly controlled postoperative pain is associated with patient dissatisfaction, impaired respiratory function, immunosuppression, prolonged ileus, delayed recovery times, inability to participate in rehabilitation, and higher healthcare costs [1, 2]. More importantly, inadequate pain control can lead to development of chronic post-surgical pain and persistent opioid use and abuse [3]. In light of the opioid epidemic, the reduction of opioid use perioperatively has become a priority for practitioners prescribing these drugs. When developing strategies to reduce opioid exposure in a rational manner, essential considerations include the ease of administration, drug toxicity, long-lasting effects, and the non-addictive potential of alternate therapies. The concept of multimodal analgesia has emerged as a means to maximize the analgesic properties of non-opioid drugs while minimizing opioid use.

Multimodal analgesia involves the administration of at least two analgesics and/or anesthetic techniques with different mechanisms of action with the goal of achieving adequate blockade of peripheral nociceptive inputs and modulation of centrally located pain pathways, when possible (Table 1) [2, 4]. Multimodal analgesia has become an essential component in the patients’ perioperative journey in its facilitation of early mobilization, early enteral nutrition, and reduced stress-related complications. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX) 2 inhibitors, ketamine, α-2 agonists, anticonvulsants, intravenous (IV) lidocaine, IV magnesium and regional anesthesia (local anesthetic infiltration, peripheral nerve blocks and neuraxial analgesia) are non-opioid based strategies commonly employed in multimodal analgesia techniques [5].

Table 1.

Commonly used non-opioid analgesics

Medication	Mechanism of Action	Recommended dose	Advantages	Disadvantages
Acetaminophen	Central COX inhibition	>50 kg: 1000 mg q6h <50 kg: 15 mg/kg q6h	Lack of respiratory, renal, cardiovascular, and bleeding effects	Hepatotoxicity at doses > 4g; Hypotension if given intravenously
Non-steroidal anti-inflammatory drugs	COX inhibition	Ketorolac: 15-30 mg q6h Celecoxib: 50-200 mg single dose.	No effect on respiratory drive	Inhibit platelet aggregation; Gastrointestinal ulcers and renal dysfunction
Ketamine	NMDA inhibition	IV bolus : 0.5 mg/kg Infusion: 0.1-0.2 mg/kg/hour	Minimal effect on respiratory drive	Sympathomimetic and psychotropic effects, increase salivation, potentially increase IOP and ICP
Gabapentinoids	Inhibition of voltage-gated calcium channel	600-1200 mg TID		Confusion and excessive sedation; potentiate respiratory depression of opioids; dose reduction required in patients with renal dysfunction
Dexmedetomidine	Central alpha-2 adrenergic agonist	IV bolus: 0.5-1 mg/kg bolus over 10 min Infusion: 0.2-1 mcg/kg/hour	Minimal effect on respiratory drive	Bradycardia and hypotension
Lidocaine	Voltage-gated sodium channel blocked and anti-inflammatory effect	IV bolus; 1.5 mg/kg Infusion: 1-2 mg/kg/hour IV	Minimal effect on respiratory drive	Local anesthetic systemic toxicity
Magnesium	NMDA inhibition	IV bolus: 30-50 mg/kg Infusion: 8-15 mg/kg/hour	Minimal effect on respiratory drive	Potentiates neuromuscular blockade; Contraindicated in renal failure
Esmolol	Central neuronal modulation and anti-inflammatory	IV bolus: 0.5 mg/kg Infusion: 5-15 μg/kg/min	Minimal effect on respiratory drive	Bradycardia and hypotension

COX: cyclooxygenase. NMDA: N-methyl-D-aspartate. TID: Three times a day.

The successful implementation of multimodal analgesia requires not only the understanding of risks and benefits of the drug, but proper communication between anesthesiologists, surgeons, and nursing personnel about each intervention. It also requires adequate communication and education of the patient to set expectations regarding the benefits of utilizing opioid-sparing techniques for pain control [6]. Other important factors include a careful assessment of patient comorbidities, type of surgery being performed, medication costs, and availability of institutional resources.

The goal of this review is to highlight the current evidence available for non-opioid medications that are commonly used in multimodal regimens. Additionally, we will provide a short comment on novel therapies that have the potential of becoming clinically available for postoperative pain management.

Conventional analgesics

Non-steroidal anti-inflammatory drugs (NSAIDs)

Through inhibition of COX-1 and COX-2 enzymes, NSAIDs block prostaglandin production, playing an important role in the reduction of pain and inflammation. COX-mediated adverse effects including platelet impairment, gastrointestinal effects, and renal dysfunction have occasionally tempered NSAID use in the perioperative period. A recent review of 32 randomized controlled trials (RCTs) examining the utility of NSAIDs as part of perioperative multimodal therapy concluded that NSAIDs (exceptions were meloxicam and piroxicam) significantly reduced opioid requirements and opioid-related side effects [7]. Serious NSAID-related adverse events reported in this review were few (gastrointestinal bleeding, bladder perforation, and transient oliguric renal failure), and none of the trials reported increased postoperative bleeding. Similarly, a systematic review of 15 studies evaluating NSAID-use in plastic surgery procedures, including breast surgery, found no risk of increased bleeding [8]. A large RCT performed by Nissen et al. comparing celecoxib (a selective COX-2 inhibitor) with ibuprofen and naproxen (non-selective COX-inhibitors) for arthritis found that celecoxib had significantly lower gastrointestinal effects compared with ibuprofen and naproxen, non-inferior cardiovascular effects compared to ibuprofen and naproxen, and lower renal events compared with ibuprofen [9]. A 2018 Cochrane review was inconclusive regarding postoperative renal function effects of NSAIDs in patients with normal kidney function [10]. Similarly, due to the limited number of studies available, further research is required to assess any adverse effects of NSAIDs on soft-tissue and bone healing [11, 12].

Acetaminophen

The lack of significant adverse respiratory, cardiovascular, and bleeding effects of acetaminophen have contributed to its widespread use as a first-line agent for pain and fever in multiple clinical settings. The exact mechanism of action of acetaminophen is unknown but believed in part to involve centrally acting COX inhibition [13]. A recent systematic review and meta-analysis of 2,635 patients, found that preoperative IV acetaminophen administration compared to placebo significantly diminished pain scores, reduced intensive care unit length of stay, and decreased the need/dose of rescue analgesics in post-craniotomy patients [14]. Similar analgesic benefits were found in meta-analyses of RCTs comparing acetaminophen versus placebo for post-cesarean, post-bariatric, and post-total joint arthroplasty surgeries [15-17]. A systematic review of seven RCTs by Remy et al., showed that adding acetaminophen orally or intravenously to morphine contributed to a significant opioid-sparing effect of 20% [18]. Despite the faster onset of action, higher peak plasma and cerebrospinal fluid concentrations of intravenous acetaminophen, multiple single-center randomized studies have concluded the equivalent efficacy of the oral versus parenteral route in terms of pain scores and opioid consumption [19-22]. Intravenous administration has more predictable pharmacokinetics; thus, certain conditions such as nil per os status, nausea and vomiting, or altered gastric absorption may warrant its use. Also, IV administration bypasses first-pass metabolism reducing exposure of acetaminophen to the liver two-fold, potentially benefiting those with hepatic dysfunction [23]. Nevertheless, acetaminophen, in toxic doses, can cause hepatic failure and even lead to death. Though oral dosing recommendations were historically a maximum of 4 grams per day, the Food and Drug Administration (FDA) suggested a reduction in this dosage to mitigate over-the-counter misuse, and as a result in 2011, the makers of Tylenol® brand of acetaminophen reduced the recommended maximum oral daily dose to 3 grams per day [24]. The maximum IV dosage, which is delivered by health care providers, is recommended at 4 grams per day. Acetaminophen use must be further limited (to less than 2 grams per day) or avoided altogether in patients with hepatitis C, alcoholism, malnutrition, and severe renal or hepatic impairment.

Ketamine

The analgesic and anesthetic properties of ketamine rely on inhibition of N-methyl-D-aspartate (NMDA) receptors, which have been implicated in chronic, ischemic, and neuropathic pain states [25, 26]. Robust evidence for its use in the acute pain setting has increased its use intraoperatively as well as postoperatively [27]. A 2018 Cochrane review of 130 studies including a wide range of surgeries concluded that ketamine reduced opioid consumption and pain scores at 24 hours and 48 hours especially after thoracic, major abdominal, and major orthopedic surgery [28]. It also reduced postoperative nausea and vomiting to a small extent, and decreased hyperalgesia [28]. Recent consensus guidelines published by the American Society of Regional Anesthesia and Pain Medicine (ASRA) highlight the evidence for the use of ketamine for acute perioperative pain. The guidelines recommend consideration of sub-anesthetic ketamine infusions (not to exceed 1 mg/kg/h) in opioid-dependent or opioid-tolerant patients having surgery, patients undergoing large painful surgery, and in patients with coexisting diseases such as sleep apnea who may respond poorly to opioid therapy [29]. Mood effects, including hallucinations, hypertension, and increased salivation, can occur with ketamine. As a result, bolus doses (up to 0.35 mg/kg), especially in the inpatient setting, should be performed with caution and intensive bedside monitoring. Current new research includes a large randomized controlled trial (ROCKet trial) testing the efficacy of ketamine in the prevention of chronic persistent postoperative pain. The study is designed to enroll 4,884 patients who will receive perioperative ketamine for up to 72 hours and expected to finish enrollment in 2022 [30]. Further studies are required to determine the role of ketamine use in patients with moderate to severe hepatic dysfunction, poorly controlled psychiatric illness, increased intraocular and intracranial pressure, pregnancy, and severe cardiovascular disease [31-34].

Gabapentinoids

Gabapentin and pregabalin, structural analogues of the neurotransmitter gamma aminobutyric acid (GABA) have been increasingly used in the perioperative setting as part of multimodal analgesia regimens. Several systematic reviews and meta-analysis of RCTs in patients having spine surgery [35], total knee arthroplasty [36], and breast cancer surgery [37], have shown that gabapentin in comparison to placebo is superior in postoperative pain reduction as well as decreasing opioid consumption and opioid-related side effects. Due to their strong association with reduced perioperative opioid use, gabapentinoids are a key non-opioid analgesic adjunct included in ERAS protocols [38-42]. Generally, ERAS protocols include single oral doses of gabapentin or pregabalin preoperatively followed by post-operative doses for the duration of the hospital stay. A common side effect, especially in elderly patients, is profound sedation, which can be mitigated by dose reduction or limitation to nighttime dosing. Increased postoperative respiratory depression has been shown as another side effect when gabapentinoids are used as part of a multimodal protocol. This finding seems to be related to the ability of gabapentinoids to potentiate respiratory depression induced by opioids[43]. As a result, precautions should be taken with use in the elderly, morbidly obese patient, or with the concomitant use of central nervous system depressants [44]. In addition, given that gabapentin has renal elimination, significant dose reduction and timing with dialysis is required in patients with renal impairment.

Dexmedetomidine

Due to the minimal effect on respiratory depression, rapid half-life, and profound analgesic and anxiolytic effects, IV dexmedetomidine has emerged as a unique adjunct for perioperative pain control [45, 40]. Dexmedetomidine is a highly selective α₂ adrenoreceptor agonist that provides anti-nociception through receptor activation in the central nervous system and spinal cord, ultimately enhancing the inhibition of pain pathways [5]. A systematic review of 30 trials assessing the analgesic efficacy of perioperative systemic α₂-agonists (clonidine or dexmedetomidine) compared with placebo showed a reduction in opioid consumption, pain intensity, and nausea after surgery with both drugs [46]. Similar significant opioid-sparing effects were found intra- and postoperatively by Liu et al. in a meta-analysis of 11 RCTs assessing the analgesic efficacy of intraoperative dexmedetomidine in patients having neurosurgery [47]. Other studies including a 2016 Cochrane systematic review of perioperative dexmedetomidine use in patients post abdominal surgery [48], a meta-analysis by Tsaousi et al. appraising the evidence of dexmedetomidine as a sedative and analgesic in spine surgery [49], and a 2018 review of dexmedetomidine use for acute pain after cardiothoracic surgery [50], all suggest opioid-sparing trends, however have been less conclusive due to low quality evidence.

Intravenous administration of dexmedetomidine has been shown to significantly prolong the duration of sensory and motor blockade of spinal anesthesia as well as reduce or prevent opioid-induced hyperalgesia [51-53]. Also, a large single-center retrospective study involving 1,260 patients by Ji et al., showed that the perioperative administration of dexmedetomidine in patients undergoing cardiac surgery significantly reduced the incidence of postoperative delirium as well as improved survival, effects attributed to the anti-inflammatory and sympatholytic properties of the drug [54]. Additionally, a meta-analysis of RCTs demonstrated that dexmedetomidine reduced the frequency and severity of postoperative nausea and vomiting compared to placebo [55]. The reduction in PONV was in adult and pediatric patients and independent of the administration mode (loading dose alone, infusion only or loading dose followed by infusion) [55]. Reported side effects of continuous dexmedetomidine infusions include hemodynamic alterations such as bradycardia and hypotension therefore continuous monitoring is required; bolus dosing requires additional vigilance [56].

Lidocaine

Lidocaine, an amide local anesthetic commonly used in regional anesthesia, has been successfully used for the treatment of chronic and neuropathic pain states as well as the prevention of chronic postsurgical pain when given systemically as an infusion [57-60]. The clinical duration of efficacy has been shown in many clinical trials to exceed the duration of the infusion by 8.5 hours or longer, suggesting that signaling mechanisms in addition to voltage-gated sodium channel blockade such as anti-inflammatory or neuronal-mediated may be involved [61, 62].

Benefits of lidocaine discussed in the chronic pain literature have sparked an interest for its use as part of multimodal analgesia regimens; however, results have been conflicting. A recent large Cochrane systematic review of 68 trials (4,525 patients) assessing the effects of perioperative IV lidocaine use on pain scores, opioid consumption, postoperative nausea, and bowel function recovery was inconclusive due to small sample size and high statistical heterogeneity [63]. The 68 trials reviewed consisted of patients undergoing abdominal surgery (22), laparoscopic abdominal surgery (20), and various other surgeries including thoracic, orthopedic, plastic, and neurosurgery (26). Though earlier smaller reviews showed some pain reduction benefit in abdominal surgery when analyzed by surgical subgroup, opioid-sparing benefits were not seen in this review [64]. Though no major neurologic or cardiac events were described in this review, nursing education regarding adverse effects, patient monitoring and appropriate resuscitation materials (including intralipid) is recommended. Ultimately, making conclusions regarding the efficacy and optimal dosing of lidocaine will require future robust larger randomized placebo-controlled trials.

Magnesium

The purported analgesic benefits of IV magnesium sulfate rely on its NMDA receptor antagonism and calcium regulation in the central nervous system. The opioid-sparing effect of magnesium has been described in multiple studies. Rodriguez-Rubio et al. concluded in their meta-analysis that perioperative magnesium provided a significant reduction in fentanyl requirement when used as an adjunct during general anesthesia [65]. A meta-analysis of 20 studies comparing perioperative IV magnesium with controls in 1,257 patients concluded that it significantly reduced postoperative opioid consumption as well as decreased early (0-4 hours) and late pain scores (24 hours) [66]. Another meta-analysis of 25 trials of 1,461 patients showed similar benefits in opioid reduction, but did not demonstrate any improvement of adding a continuous infusion postoperatively versus administration of an intraoperative bolus dose only [67].

By inhibiting calcium channel blockers, magnesium potentiates neuromuscular blockade, prolonging the clinical duration and the recovery time. Other side effects of magnesium include headache, dizziness, flushing, nausea and muscle weakness [68]. Reporting is limited, however, systemic perioperative magnesium does not appear to increase clinically significant cardiovascular effects of bradycardia and hypotension. Though studies using neuraxial magnesium have shown benefits in terms of decreased opioid consumption, increased time until analgesic request, and prolonged duration of sensory and motor blockade, poor review of its neurologic safety profile and limited animal research in this area suggests the need for caution and further study before its use for this indication [69, 70].

Esmolol

The exact mechanisms of anti-nociception of esmolol, an ultra-rapid acting β-1 receptor agonist, are largely unknown; however, it has been hypothesized that central neuronal modulation and anti-inflammatory properties are involved [71]. A 2018 meta-analysis of 23 RCTs comparing esmolol to placebo, opioid, or local anesthetic demonstrated that the beta-blocker decreased intraoperative and postoperative opioid consumption in the post-anesthesia recovery unit with an effect similar or greater than other commonly used adjuncts [72]. All of the included studies administered an IV loading dose followed by an infusion for the duration of the surgery and no studies found clinically significant hypotension or bradycardia at the doses administered (Table 1).

Given the hemodynamic profile which results after esmolol administration, intraoperative avoidance has been suggested as a reason for its opioid-sparing effects. This, along with a lack of a fully understood mechanism for its anti-nociception, has led some experts to be concerned about masking the signs of pain with esmolol use. [73-75].

Novel analgesics

Mu-opioid receptor (MOR) agonists are potent analgesics, but unfortunately are highly addictive. Recent research has revealed that opioid receptors are more complex than previously appreciated, possibly explaining the difficulties of developing an ideal molecule that offers analgesia and lacks side effects (e.g. abuse, dependence, respiratory depression, constipation and tolerance). These unwanted side effects have motivated scientists to pursue new pharmacologic means to selectively activate pathways to maximize analgesic effects (Table 2).

Table 2.

Novel analgesics

Medication	Mechanism of action	Advantages	Disadvantages
Opioid Biased agonist	Opioid ligand that preferentially signals β-arrestin over G protein signaling.	Effective analgesia with less constipation, nauseas, vomit and respiratory depression.	Abuse potential and tolerance.
Peripherally acting opioids	Activation of Mu peripheral receptor in the presence of tissue injury and inflammation.	Effective analgesia with less constipation, nausea, vomit, respiratory depression. Lack of addiction potential	Only in vivo models.
Nitric oxide synthase inhibitors	Activation of soluble guanyl cyclase and the generation of cyclic GMP. Promotion towards anti-inflammatory (IL-10) rather than the pro-inflammatory (IL-1 α and IL-1 β) profile.	Lack of constipation, nauseas, vomit, respiratory depression, addiction and tolerance.	Benefits only migraine Cardiovascular side effects such as hypotension.
Calcitonin gene-related peptide (CGRP) receptor antagonists	Antagonists of the calcitonin gene-related peptide receptor	Lack of cardiovascular side effects such as changes blood pressure or heart rate.	Benefits only migraine Elevated liver enzymes
IL-6 receptor antagonists	Inhibits IL-6 receptor	Selectively for inflammatory pain	Risk of infection Increases in serum total cholesterol
Transcription factor decoy	Targets and inhibits key transcription factors involved in the pathogenesis of pain	Reduces mechanical hypersensitivity over a month (animal model)	Lack of large human studies Unknown side effects
Ribonucleic acid interference	Inhibits the translation of proteins from mRNA	Long-term silencing of pain genes using a vector system	Only animal studies Unknown side effects

mRNA: messenger ribonucleic acid. RNAi

Opioid Biased Agonism

It is well established that MORs are G Protein-Coupled Receptors (GPCRs) [76]. In most cases, opioid agonists can efficiently activate both G protein and β-arrestin dependent signaling (figure) [77]. Biased agonism or functional selectivity is an appealing concept where an opioid ligand preferentially signals one intracellular pathway (G protein depending signaling) over another (β-arrestin dependent signaling) [78]. For instance, morphine-induced side effects such as constipation and respiratory depression are reduced in β-arrestin knockout mice [79]. These observations suggest that β-arrestin modulates opioid side effects and G protein modulates analgesia.

Figure. Mechanism of action of novel analgesic.

The figure illustrates the different mechanisms of action of novel analgesics. While some of them have shown efficacy in animal models, none of them has been introduce for routine clinical postoperative pain management. Transcription factor decoy therapies have been tested in phase II clinical trials.

Oliceridine or TRV130 is the first G protein-biased MOR agonist that has undergone investigation in clinical trials. Oliceridine displays a preference for the G protein pathway over β-arrestin signaling [80]. Oliceridine appears to be a promising medication given the effective analgesia and favorable side effect profile in pre-clinical rodent models [81]. Along with this finding, a randomized, double-blind, placebo-controlled, crossover study of healthy volunteers showed that oliceridine produced greater analgesic effect than morphine with better tolerability (specifically less respiratory depression, nausea and vomiting) [82]. Additionally APOLO-2, a randomized phase III study (NCT02820324), evaluated the efficacy and safety of oliceridine against morphine (1 mg) and placebo for acute pain following abdominoplasty [83]. All Oliceridine dosing regimens (0.1, 0.35, or 0.5 mg) provided superior analgesia compared to placebo, and 0.35 - 0.5 mg of oliceridine showed equipotency compared to morphine. The most common side effects reported for oliceridine were nausea and vomiting. Respiratory events were significantly lower with 0.1 mg, but not different with 0.35 mg and 0.5 mg of oliceridine compared to morphine [84]. In 2018, the FDA rejected oliceridine for the treatment of moderate to severe pain, given concerns regarding QT prolongation and an inadequately sized safety database. TRV734 is an oral analog of oliceridine that has shown a favorable profile in clinical settings. A study in healthy volunteers suggested that TRVT34 has good oral bioavailability [85], but no studies have tested its efficacy in the context of surgical pain. Lastly, PZM21 is another G protein-biased MOR agonist that produces analgesia with lower addictive potential in mice as suggested by the lack of rewarding or reinforcing properties; however, repeated administration led to tolerance [86].

Designing a biased ligand that promotes effective analgesia and an improved safety profile is an ongoing area of research requiring further study. Ultimately, the role of these new agents in the context of multimodal analgesia is still unknown.

Peripherally acting opioids

Recent advances in the understanding of opioid receptors and their clinical effects have raised the question of whether limited peripheral activation of MOR (with restricted access to the central nervous system) could result in effective analgesia and a lower risk of tolerance and respiratory depression. In the presence of lower pH and acidity (commonly present in tissue injury and inflammation, figure) opioid receptors become expressed on peripheral afferent nerve terminals. Thus, protonated ligands that target pH sensitive ligands can selectively activate MOR under inflammation and tissue injury. Rodriguez–Gaztelumendi et al. studied the behavior of MOR in inflammatory states and observed that N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NEEP) selectively activates peripheral MOR in inflamed tissue [87]. NEEP had a similar analgesic effect as fentanyl and did not produce side effects such as respiratory depression, sedation, addiction, and constipation in models of neuropathic and abdominal pain [87]. The use of NEEP in humans has not been explored yet.

Nitric oxide synthase inhibitors

Nitric oxide (NO) is a highly soluble and diffusible molecule produced by NO synthase from L-arginine [88]. Within the nervous system, NO is responsible for many processes, including regulation of synaptic plasticity in different disease processes including neuropathic pain [89]. Unlike other endogenous mediators, NO cannot be stored in vesicles, and therefore, its function is tightly regulated by the expression and activity of NO synthase (NOS) [89].

Nitric oxide acts on a number of target enzymes and proteins. The most important signaling pathway stimulated by NO is the activation of soluble guanylyl cyclase and the generation of cyclic guanosine monophosphate (cGMP) [88]. Nitric oxide also participates in the inflammatory response [90] and has been shown to interact with cyclooxygenase [91]. A growing body of evidence indicates that NO and cGMP contribute to the processing of nociceptive signaling in the spinal cord. For instance, Staunton et al. suggested that NO synthase inhibitor (1400W) ameliorated hypersensitivity in a neuropathic pain rat model (figure). They proposed that the NO synthase inhibitor exerts its analgesic effects by reducing iNO ultimately tipping the balance of cytokines towards the anti-inflammatory (IL-10) rather than the pro-inflammatory (IL-1 α and IL-1 β) state [92].

Despite their great theoretical value, human studies of selective NOS inhibitors have only shown some benefit for acute migraine headaches and minimal benefit in the prevention of headaches. Unfortunately, cardiovascular adverse events and unfavorable pharmacokinetics have raised concerns for their use in clinical practice [93, 94].

Calcitonin gene-related peptide (CGRP) receptor antagonists

CGRP is a key modulator in neurogenic inflammatory pain. Olcegepant was the first CGRP antagonist studied as a potential treatment for migraines (2.5 mg/day) and found to be an effective and well-tolerated drug [95]. Unfortunately, the medication is not available for commercial use as it cannot be administrated orally. Telcagepant (300 mg/day) is also effective for the acute treatment of migraine headaches, however its use was associated with a significant increase in liver function enzymes [96]. Currently, there are two CGRP receptors antagonists, rimegepant and ubrogepant, that are in Phase III clinical trials for the acute treatment of migraines. Currently the efficacy of CGRP receptor antagonists for the treatment of surgical pain is unknown.

Interleukin (IL-6) receptor antagonists

IL-6 is a critical modulator of inflammatory and neuropathic pain. Boettger et al. studied the role of IL-6 for antigen-induced arthritic pain in rats. The authors reported that intra-articular administration of sgp130 (IL-6 antagonist) caused a significant long-term antinociceptive effect [97]. Tocilizimab, an IL-6 neutralizing antibody approved for the treatment of juvenile idiopathic arthritis and rheumatoid arthritis, has also shown to be effective for the treatment of radicular pain. Ohtori et al. observed that the direct application of anti-IL-6 receptor monoclonal antibody into the spinal nerves was more effective than dexamethasone to reduce lower back and leg pain, as well as leg numbness caused by spinal stenosis [98]. Given that this cytokine is also involved in the modulation of surgical pain, new indications may be on the horizon for IL-6 antagonists [99].

Gene therapy for acute pain

Transcription factor decoy

Gene therapy has evolved as a promising and exciting concept in pain therapy. Transcription factor proteins bind to specific DNA sequences located in promoter/enhancer regions of the genes they regulate. Transcription factor (TF) decoys represents a new class of therapeutic agents that can target and inhibit key transcription factors involved in the pathogenesis of pain [100]. Epidermal growth receptor factor (EGRF-1) is a transcription factor essential for the regulation of pain pathways. The activation of EGFR-1 triggers long term transcriptional changes necessary for the development of pain and mechanical hypersensitivity. Based on these observations, Mamet et al. studied the effect of a single intrathecal administration of AYX1 (DNA decoy that inhibits EGR1) during the peri-operative period [101]. The investigators found that AYX1 produced a substantial reduction of mechanical hypersensitivity (60-70% compared to control) in models of acute incisional, inflammatory, and chronic neuropathic pain [101]. Three clinical studies have evaluated the efficacy of AXY1 in the treatment of postoperative pain after knee replacement surgery (ClinicalTrials.gov: NCT01731730, NCT02081703 and NCT02807428); the results of which have not yet been released.

Ribonucleic acid interference

Ribonucleic acid interference (RNAi) is a mechanism to regulate endogenous gene expression in which the messenger RNA (mRNA) is blocked from translating into a protein (figure) [102]. There are at least two distinct mechanisms of RNAi. First, micro RNA (miRNA) are endogenous, single-strand, non-coding RNA molecules that can regulate hundreds of genes [103]. Several miRNAs, mainly those involved in inflammation, have shown promising results in animal models of incisional pain [104-113]. For instance, intraplantar injection of miR-203 reversed hyperalgesia by modulating phospholipase A2 activating protein [114]. The second mechanism involves small interfering RNAs (siRNAs) which have a single mRNA target [115]. Knockout of the SCN9A gene via RNAi-lentivirus three days before plantar incision decreased Nav1.7 expression in dorsal root ganglia and alleviated postoperative pain in rats [116].

Before considering gene therapies as part of multimodal strategies, several important questions need to be answered including the targeted gene or genes, type of surgery, and the possible implications of co-administration with traditional analgesics. Polygenic therapy or multimodal gene regulation is an attractive alternative to provide analgesia in surgical pain. One could hypothesize that genes highly regulated in models of neuropathic pain should be considered in surgeries associated with high rates of post-surgical neuropathic pain (i.e., mastectomies or thoracotomies). However, animal models of neuropathic pain do not necessarily translate into human conditions of postoperative neuropathic pain [117]. Another consideration is the route and timing of administration of miRNA or siRNAs. Experimental studies suggest that multiple injections of RNAi based therapies (hours or days before surgery) may be needed to facilitate downregulation of proteins; therefore, downregulation of nociceptors only expressed after surgery may be a more attractive therapy. While RNAi therapy is rapidly expanding in oncology medicine, its clinical use in acute pain medicine is still in early stages.

Conclusion

The prescription of opioids for postoperative pain management, particularly in chronic non-cancer pain, has increased more than fourfold in the United States since the mid-1990s. Opioids play an important role in perioperative analgesia, however finding the lowest effective dose while minimizing side effects is a critical goal for multimodal analgesia regimens. Multimodal analgesia is highly recommended in the perioperative period due to several advantages including: 1) increasing efficacy through synergistic or additive effects, 2) decreasing the dose of each respective agent (including the amount of opioids), and 3) diminishing the risk of unwanted side effects. While physicians have embraced opioid sparing multimodal therapies including ERAS protocols perioperatively, it is important to highlight that prescribing patterns of physicians regarding discharge opioids have only recently started to change [118-120]. Physician education regarding the proper management of these oral opioids for outpatient use and follow-up of high-risk patients is paramount to reduce opioid withdrawal and misuse. Furthermore, effective communication with patients with regards to the appropriate use of opioids, as well as multimodal analgesia, is critical for success.

In conclusion, opioids are potent analgesics that should be considered in conjunction with non-opioid adjuncts for the treatment of postoperative pain. Curbing the opioid epidemic will ultimately require a dedicated and organized multidisciplinary approach. Physicians should focus on education as well as allocation of resources to ensure appropriate delivery of multimodal therapy and development of novel treatments with improved safety profiles.